Hippocampal-Dependent Cognitive Dysfunction following Repeated Diffuse Rotational Brain Injury in Male and Female Mice

Abstract

Cognitive dysfunction is a common, often long-term complaint following acquired traumatic brain injury (TBI). Cognitive deficits suggest dysfunction in hippocampal circuits. The goal of the studies described here is to phenotype in both male and female mice the hippocampal-dependent learning and memory deficits resulting from TBI sustained by the Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA) device-a model that delivers both a contact-concussion injury as well as unrestrained rotational head movement. Mice sustained either sham procedures or four injuries (0.7 J, 24-h intervals). Spatial learning and memory skills assessed in the Morris water maze (MWM) approximately 3 weeks following injuries were significantly impaired by brain injuries; however, slower swimming speeds and poor performance on visible platform trials suggest that measurement of cognitive impairment with this test is confounded by injury-induced motor and/or visual impairments. A separate experiment confirmed hippocampal-dependent cognitive deficits with trace fear conditioning (TFC), a behavioral test less dependent on motor and visual function. Male mice had greater injury-induced deficits on both the MWM and TFC tests than female mice. Pathologically, the injury was characterized by white matter damage as observed by silver staining and glial fibrillary acidic protein (astrogliosis) in the optic tracts, with milder damage seen in the corpus callosum, and fimbria and brainstem (cerebral peduncles) of some animals. No changes in the density of GABAergic parvalbumin-expressing cells in the hippocampus, amygdala, or parietal cortex were found. This experiment confirmed significant sexually dimorphic cognitive impairments following a repeated, diffuse brain injury.

Biological Connection of Psychological Stress and Polytrauma under Intensive Care: The Role of Oxytocin and Hydrogen Sulfide

“…We previously showed that the aggravated posttraumatic pulmonary and systemic inflammation in CSE −/− mice was more pronounced in male than in female animals [127]. This is in line with the most recent data that white matter damage and cognitive dysfunction was more pronounced in male than in female mice [213]. Moreover, mortality after TBI is most pronounced in the elderly, male patient [214,215], and, finally, the incidence and morbidity of ASDH is highest in this population [216,217].…”

Lateral Fluid Percussion Injury Causes Sex-Specific Deficits in Anterograde but Not Retrograde Memory

“…Sex-specific differences in cued fear response have also been detected after repetitive brain injury-with males freezing less than females after TBI (Tucker et al, 2019(Tucker et al, , 2021. To date, this is the only report showing that lateral FPI results in sex-specific cued fear memory retention deficits.…”

Measuring Anxiety-Like Behaviors in Rodent Models of Traumatic Brain Injury

“…As unconditioned tests of anxiety partly rely on discrimination between light and darkness, the visual system plays a role in task performance. Deficits in visual acuity have been demonstrated following concussive, weight-drop, CHIMERAand blast-induced TBI in rodents (Xu et al, 2016;Desai et al, 2020;Evans et al, 2021;Morriss et al, 2021;Tucker et al, 2021), but a basic light/dark discrimination ability may be intact and adequate for performance. Filgueiras and colleagues demonstrated that rats no longer avoid open arms of the EPM if they are enclosed with clear walls, suggesting the absence of physical walls is the anxiogenic factor (Filgueiras et al, 2014).…”