Sex-Dependent Pathology in the HPA Axis at a Sub-acute Period After Experimental Traumatic Brain Injury

Bromberg, Caitlin E.; Condon, Andrew M; Ridgway, Samantha W; Krishna, Gokul; Garcia-Filion, Pamela; Adelson, P. David; Rowe, Rachel K.; Thomas, Theresa Currier

doi:10.3389/fneur.2020.00946

Cited by 30 publications

(21 citation statements)

References 131 publications

(165 reference statements)

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“…Therefore, all 81 male rats were processed at same time and if we also included females, it would become practically infeasible to process such a large number of animals. However, there is increasing research demonstrating that there are sex differences in behavioral and pathological outcomes after a TBI in the clinic and laboratory (90)(91)(92)(93)(94). Research has shown that males exhibit greater white matter damage than that observed in females after a TBI using diffusion-tensor imaging (90).…”

Section: Discussionmentioning

confidence: 99%

Age-at-Injury Determines the Extent of Long-Term Neuropathology and Microgliosis After a Diffuse Brain Injury in Male Rats

et al. 2021

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Traumatic brain injury (TBI) can occur at any age, from youth to the elderly, and its contribution to age-related neuropathology remains unknown. Few studies have investigated the relationship between age-at-injury and pathophysiology at a discrete biological age. In this study, we report the immunohistochemical analysis of naïve rat brains compared to those subjected to diffuse TBI by midline fluid percussion injury (mFPI) at post-natal day (PND) 17, PND35, 2-, 4-, or 6-months of age. All brains were collected when rats were 10-months of age (n = 6–7/group). Generalized linear mixed models were fitted to analyze binomial proportion and count data with R Studio. Amyloid precursor protein (APP) and neurofilament (SMI34, SMI32) neuronal pathology were counted in the corpus callosum (CC) and primary sensory barrel field (S1BF). Phosphorylated TAR DNA-binding protein 43 (pTDP-43) neuropathology was counted in the S1BF and hippocampus. There was a significantly greater extent of APP and SMI34 axonal pathology and pTDP-43 neuropathology following a TBI compared with naïves regardless of brain region or age-at-injury. However, age-at-injury did determine the extent of dendritic neurofilament (SMI32) pathology in the CC and S1BF where all brain-injured rats exhibited a greater extent of pathology compared with naïve. No significant differences were detected in the extent of astrocyte activation between brain-injured and naïve rats. Microglia counts were conducted in the S1BF, hippocampus, ventral posteromedial (VPM) nucleus, zona incerta, and posterior hypothalamic nucleus. There was a significantly greater proportion of deramified microglia, regardless of whether the TBI was recent or remote, but this only occurred in the S1BF and hippocampus. The proportion of microglia with colocalized CD68 and TREM2 in the S1BF was greater in all brain-injured rats compared with naïve, regardless of whether the TBI was recent or remote. Only rats with recent TBI exhibited a greater proportion of CD68-positive microglia compared with naive in the hippocampus and posterior hypothalamic nucleus. Whilst, only rats with a remote brain-injury displayed a greater proportion of microglia colocalized with TREM2 in the hippocampus. Thus, chronic alterations in neuronal and microglial characteristics are evident in the injured brain despite the recency of a diffuse brain injury.

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Section: Discussionmentioning

confidence: 99%

Age-at-Injury Determines the Extent of Long-Term Neuropathology and Microgliosis After a Diffuse Brain Injury in Male Rats

et al. 2021

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“…76,78 Further, sex differences exist in post-injury neuroinflammation, in terms of Iba-1 staining and microglia morphology, over time and across brain regions after midline FPI and controlled cortical impact (CCI). 79,80 Ultimately, the mechanics of TBI must consider the skull, in addition to the influence of sex, gender, and physiological hormones.…”

Section: Discussionmentioning

confidence: 99%

Spatial Distribution of Neuropathology and Neuroinflammation Elucidate the Biomechanics of Fluid Percussion Injury

Beitchman

Lifshitz

Harris

et al. 2021

Neurotrauma Reports

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Diffuse brain injury is better described as multi-focal, where pathology can be found adjacent to seemingly uninjured neural tissue. In experimental diffuse brain injury, pathology and pathophysiology have been reported far more lateral than predicted by the impact site. We hypothesized that local thickening of the rodent skull at the temporal ridges serves to focus the intracranial mechanical forces experienced during brain injury and generate predictable pathology. We demonstrated local thickening of the skull at the temporal ridges using contour analysis on magnetic resonance imaging. After diffuse brain injury induced by midline fluid percussion injury (mFPI), pathological foci along the anterior-posterior length of cortex under the temporal ridges were evident acutely (1, 2, and 7 days) and chronically (28 days) post-injury by deposition of argyophilic reaction product. Area CA3 of the hippocampus and lateral nuclei of the thalamus showed pathological change, suggesting that mechanical forces to or from the temporal ridges shear subcortical regions. A proposed model of mFPI biomechanics suggests that injury force vectors reflect off the skull base and radiate toward the temporal ridge, thereby injuring ventral thalamus, dorsolateral hippocampus, and sensorimotor cortex. Surgically thinning the temporal ridge before injury reduced injury-induced inflammation in the sensorimotor cortex. These data build evidence for temporal ridges of the rodent skull to contribute to the observed pathology, whether by focusing extracranial forces to enter the cranium or intracranial forces to escape the cranium. Pre-clinical investigations can take advantage of the predicted pathology to explore injury mechanisms and treatment efficacy.

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“…Basic science and understanding of molecular mechanisms in this area are also lacking in pediatrics. While there are several studies that address pituitary dysfunction following TBI (151)(152)(153)(154)(155)(156)(157), these studies have only been done in adult rats. Greco et al, utilized an adolescent mild rTBI model to examine hypopituitarism following TBI.…”

Section: Hormonalmentioning

confidence: 99%

Pathophysiology of Pediatric Traumatic Brain Injury

et al. 2021

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The national incidence of traumatic brain injury (TBI) exceeds that of any other disease in the pediatric population. In the United States the Centers for Disease Control and Prevention (CDC) reports 697,347 annual TBIs in children ages 0–19 that result in emergency room visits, hospitalization or deaths. There is a bimodal distribution within the pediatric TBI population, with peaks in both toddlers and adolescents. Preclinical TBI research provides evidence for age differences in acute pathophysiology that likely contribute to long-term outcome differences between age groups. This review will examine the timecourse of acute pathophysiological processes during cerebral maturation, including calcium accumulation, glucose metabolism and cerebral blood flow. Consequences of pediatric TBI are complicated by the ongoing maturational changes allowing for substantial plasticity and windows of vulnerabilities. This review will also examine the timecourse of later outcomes after mild, repeat mild and more severe TBI to establish developmental windows of susceptibility and altered maturational trajectories. Research progress for pediatric TBI is critically important to reveal age-associated mechanisms and to determine knowledge gaps for future studies.

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Sex-Dependent Pathology in the HPA Axis at a Sub-acute Period After Experimental Traumatic Brain Injury

Cited by 30 publications

References 131 publications

Age-at-Injury Determines the Extent of Long-Term Neuropathology and Microgliosis After a Diffuse Brain Injury in Male Rats

Age-at-Injury Determines the Extent of Long-Term Neuropathology and Microgliosis After a Diffuse Brain Injury in Male Rats

Spatial Distribution of Neuropathology and Neuroinflammation Elucidate the Biomechanics of Fluid Percussion Injury

Pathophysiology of Pediatric Traumatic Brain Injury

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