Greater neurodegeneration and behavioral deficits after single closed head traumatic brain injury in adolescent versus adult male mice

Abstract

Traumatic brain injury (TBI) is a major public health concern affecting 2.8 million people per year in the United States, of whom about 1 million are children under 19 years old. Animal models of TBI have been developed and used in multiple ages of animals, but direct comparisons of adult and adolescent populations are rare. The current studies were undertaken to directly compare outcomes between adult and adolescent male mice, using a closed head, single‐impact model of TBI. Six‐week‐old adolescent and 9‐week‐old adult male mice were subjected to mild–moderate TBI. Histological measures for neurodegeneration, gliosis, and microglial neuroinflammation, and behavioral tests of locomotion and memory were performed. Adolescent TBI mice have increased mortality (Χ2 = 20.72, p < 0.001) compared to adults. There is also evidence of hippocampal neurodegeneration in adolescents that is not present in adults. Hippocampal neurodegeneration correlates with histologic activation of microglia, but not with increased astrogliosis. Adults and adolescents have similar locomotion deficits after TBI that recover by 16 days postinjury. Adolescents have memory deficits as evidenced by impaired novel object recognition between 3–4 and 4–16 days postinjury (F1,26 = 5.23, p = 0.031) while adults do not. In conclusion, adults and adolescents within a close age range (6–9 weeks) respond to TBI differently. Adolescents are more severely affected by mortality, neurodegeneration, and inflammation in the hippocampus compared to adults. Adolescents, but not adults, have worse memory performance after TBI that lasts at least 16 days postinjury.

Indirect traumatic optic neuropathy after head trauma in adolescent male mice is associated with behavioral visual impairment, neurodegeneration, and elevated endoplasmic reticulum stress markers at acute and subacute times

“…Both animal and human studies of TON are typically conducted in adult populations (e.g., due to higher incidence in military personnel). As we and others have previously shown that outcome differences between mice separated by as little as two weeks of age arise after mild TBI in memory performance, mortality, and severity of brain pathophysiology [26][27][28][29][30][31][32] it is, therefore, likely that these differences are also present across age groups in the visual system. Moreover, studies on optic nerve injury have only recently begun to analyze central projections of the optic nerve like the LGN [17,21,33,34], the SC [21,23], and the supra-oculomotor nucleus and caudate [21] but none have been conducted in an adolescent population.…”

“…We have previously reported degeneration in the optic tract, lateral geniculate nucleus, and superior colliculus within one week after TBI in adult male mice, but TON has not yet been studied in an adolescent population. [24] [26][27][28][29][30][31][32]In the current studies we expand our previous findings in adolescent mice, and include measures of retinal ganglion cell loss, changes to visual acuity, and changes in subcortical targets of the optic nerve both one week and one month after injury.…”

“…For histologic analysis of brain tissue, mice were euthanized using Fatal Plus® 7 days and 30 post-injury as previously described. [26] Sections were stained using Fluoro-Jade B or fluorescent immunohistochemistry. Fluoro-Jade B (Histo-Chem, Jackson, AR; cat# 1FJB), a marker for degenerating neurons and axons, [45] was used according to the manufacturer's directions.…”

Neuroprotective effects of flavone luteolin in neuroinflammation and neurotrauma

“…TBI is a significant public health concern affecting 2.8 million people per year in the United States. 1 "TBI is defined as an alteration in brain function, or other evidence of brain pathology, caused by an external force (for example, falls, assaults, motor vehicle accidents, sports injuries). Non-TBI (acquired brain injury) is due to internal factors such as stroke, pressure from a tumor, lack of oxygen (heart attack), infections such meningitis, seizure, neurotoxins, encephalitis, and drugs (Brain Injury Association, Fairfax, VA)."…”

“…Neuroinflammatory response and neuroinflammation are critical events in the pathogenesis of traumatic brain injury (TBI). TBI is a significant public health concern affecting 2.8 million people per year in the United States 1 . “TBI is defined as an alteration in brain function, or other evidence of brain pathology, caused by an external force (for example, falls, assaults, motor vehicle accidents, sports injuries).…”