Traumatic Brain Injury in Young Rats Leads to Progressive Behavioral Deficits Coincident with Altered Tissue Properties in Adulthood

Abstract

Traumatic brain injury (TBI) affects many infants and children, and results in enduring motor and cognitive impairments with accompanying changes in white matter tracts, yet few experimental studies in rodent juvenile models of TBI (jTBI) have examined the timeline and nature of these deficits, histologically and functionally. We used a single controlled cortical impact (CCI) injury to the parietal cortex of rats at post-natal day (P) 17 to evaluate behavioral alterations, injury volume, and morphological and molecular changes in gray and white matter, with accompanying measures of electrophysiological function. At 60 days post-injury (dpi), we found that jTBI animals displayed behavioral deficits in foot-fault and rotarod tests, along with a left turn bias throughout their early developmental stages and into adulthood. In addition, anxiety-like behaviors on the zero maze emerged in jTBI animals at 60 dpi. The final lesion constituted only *3% of brain volume, and morphological tissue changes were evaluated using MRI, as well as immunohistochemistry for neuronal nuclei (NeuN), myelin basic protein (MBP), neurofilament-200 (NF200), and oligodendrocytes (CNPase). White matter morphological changes were associated with a global increase in MBP immunostaining and reduced compound action potential amplitudes at 60 dpi. These results suggest that brain injury early in life can induce long-term white matter dysfunction, occurring in parallel with the delayed development and persistence of behavioral deficits, thus modeling clinical and longitudinal TBI observations.

Repeated Pediatric Concussions Evoke Long-Term Oligodendrocyte and White Matter Microstructural Dysregulation Distant from the Injury

“…There was no evidence of memory deficits, as measured by the discrimination index, or changes in depression-like behaviors. Although additional studies may be required to fully elucidate the behavioral sequelae of pediatric smTBI and rmTBI, our results reflect long-term adaptive and social deficits observed in a variety of pediatric TBI models both clinically [60-62] and experimentally [6, 63]. Our findings also provide the confirmatory evidence that the chosen model of pediatric mTBI is clinically relevant in producing long-term behavioral outcomes that are observed in the clinical cases.…”

Age-Dependent Responses Following Traumatic Brain Injury

“…The number of synapses at these time points is greater, and pruning events follow to decrease the number of synapses [74][75][76]. In addition, myelination is an ongoing process that continues well into adulthood [66]; atypical development of these processes as a result of TBI may significantly impact synaptic reorganization and long-term neurobehavioral development [77][78][79]. Ajao and colleagues found that TBI in rats at P17 resulted in measurable deficits in motor performance on the rotarod and foot faults at 60 days post-injury well into adulthood [77].…”

The Diagnosis and Management of Concussion in Children and Adolescents

“…31 Injury to the young, developing brain may be associated with greater risk of longterm functional impairments because of altered neuronal plasticity and immature myelination. 32,33 Following a concussive injury, there is a brief temporal window of increased concussion vulnerability in the animal model that appears to resolve gradually during 7-10 days. Longhi and colleagues demonstrated that adult mice with concussive injuries had significantly greater functional impairments with repeat injuries at 3 or 5 days compared with 7 days, suggesting that the vulnerability to repeat concussion in the animal model diminishes within 7 days from the initial TBI.…”