Hippocampal cognitive impairment in juvenile rats after repeated mild traumatic brain injury
Introduction
Any biomechanical force that results in a movement of the brain in the skull can produce a traumatic brain injury (TBI). This type of injury has recently received increased attention, with a focus on its epidemiology, variables affecting injury severity, and the potential for long-term negative consequences [[1], [2], [3], [4], [5]]. There are several classes of TBI, and, while none are truly “minor”, approximately 80–90% of all head injuries can be classified as “mild” (mTBI; also called concussion) [6]. An mTBI is a unique neurological syndrome that has an abrupt onset and can include a number of clinical symptoms (headache, dizziness, nausea, memory deficits, fatigue, balance problems, attention deficits, sleep disturbances, etc.). Gross structural pathology does not occur in mTBI, and brain imaging is normally used to rule out severe TBI, rather than to detect mTBI [7]. Cognitive impairments and subjective complaints are the most prominent features of mTBI [8,9]; with memory loss, difficulty learning, and anxiety being common sequelae [10].
In the last decade there has been a growing awareness that after experiencing an initial mTBI, individuals are more at risk for repeated mTBI (r-mTBI) and increased injury severity [3,[11], [12], [13]]. Thus, while a single concussion may not cause overt or long-lasting structural and functional deficits, the summation of multiple mTBI events may be a non-linear process that could lead to more severe injuries and greater long-term cognitive alterations. It is important to note that children and youth (< 20 years old) are amongst the most likely to sustain an mTBI [14]. This age group can be particularly susceptible to incurring an mTBI as the sensory and motor systems responsible for head stability are not fully established (e.g. development of neck muscle strength and tone, head positioning, etc.) [15,16]. Moreover, any injury may have functional consequences for the juvenile brain, as it can dramatically alter the capacity for synaptic reorganization and myelination that normally occurs during this period [[17], [18], [19], [20], [21]].
The hippocampus is a brain region that appears to be vulnerable to mTBI [[22], [23], [24], [25], [26], [27], [28]] and has been implicated in several cognitive and emotional processes associated with r-mTBI, including learning, memory and anxiety dysfunction [[28], [29], [30]]. In order to increase our understanding of the pathophysiology of r-mTBI and identify robust biomarkers, it is important to develop appropriate animal models that replicate the signs and symptoms observed in clinical populations. In the current study, we use a recently described awake close head injury model (ACHI) to induce r-mTBI [[31], [32]]. We then examined animals for cognitive and sensorimotor deficits following r-mTBI using an array of behavioural tests for animals that were analogous to those used clinically in the SCAT5 [34]. We show that the ACHI model produces acute neurological deficits similar to the ones observed in the human clinical populations, that hippocampal-dependent spatial learning and memory are impaired following r-mTBI, and that these cognitive impairments are observed in the absence of motor deficits or increases in anxiety-like behaviour.
Section snippets
Animal generation and procedures
All animal procedures were approved by the Animal Care Committee at the University of Victoria and performed in accordance with the guidelines set by the Canadian Council for Animal Care. Long-Evans female rats (Charles River Laboratories, St. Constant, PQ, Canada) were paired with proven male breeders (250–275 grams; Post-Natal Day (PND) 100–150) and plug checks were performed to confirm pregnancies. Care was taken not disturb the Dam and any new litter of pups for the first
Consciousness assessment and neurological assessment following r-mTBI
Immediately after each ACHI or sham procedure three indicators of LOC (apnea, toe pinch reflex, and righting reflex) were assessed. As expected, subjects in the sham group did not show signs of LOC for any of the three indicators (Fig. 1A, B). Apnea was not observed following the ACHI procedure in any of the subjects in any condition (data not shown). The total latency to toe pinch reflex was the average latency to respond, after each injury, for all animals in the group. As shown in Fig. 1A,
Discussion
In the current study we examined r-mTBI by administering the ACHI procedure 8 times over a four day period. We show that each administration of the ACHI procedure produces acute neurological deficits, similar in nature to concussion symptoms observed clinically, and that these symptoms can be quantified using a 4-point NAP scoring system. The results from the animals used in these experiments are in agreement with previous data [31], indicating that multiple repetitions of the ACHI procedure
Author contributions statement
C.P. and B.R.C. designed experiments and wrote the manuscript. C.P. and J.T.P. induced traumatic brain injuries and performed behavioural testing. S.P assisted in behavioural testing. C.P ran statistical analyses.
CRediT authorship contribution statement
Cristina Pinar: Conceptualization, Formal analysis, Investigation, Methodology, Writing - original draft. Juan Trivino-Paredes: Conceptualization, Methodology, Writing - review & editing. Samantha T. Perreault: Methodology. Brian R. Christie: Supervision, Project administration, Funding acquisition, Resources, Conceptualization, Methodology, Writing - review & editing, Data curation.
Declaration of Competing Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Acknowledgements
This work was supported by funding from NSERC, CIHR and CFI to BRC. CP was supported by Agusti Pedro i Pons Foundation. The authors would like to extend their gratitude to Dan McIlvaney for assistance in developing and printing the helmets described in this report. The authors would also like to thank Chris Secord in the University of Victoria Faculty of Science Machine Shop for their assistance in and designing and developing the impactor tips.
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