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. 2021 Mar;38(5):555-565.
doi: 10.1089/neu.2020.7267. Epub 2020 Sep 16.

Early Life Stress Exacerbates Outcome after Traumatic Brain Injury

Chantal M Sanchez  1 , David J Titus  1 , Nicole M Wilson  1 , Julie E Freund  1 , Coleen M Atkins  1
Affiliations

Early Life Stress Exacerbates Outcome after Traumatic Brain Injury

Chantal M Sanchez et al. J Neurotrauma. 2021 Mar.

Abstract

The neurocognitive impairments associated with mild traumatic brain injury (TBI) often resolve within 1-2 weeks; however, a subset of people exhibit persistent cognitive dysfunction for weeks to months after injury. The factors that contribute to these persistent deficits are unknown. One potential risk factor for worsened outcome after TBI is a history of stress experienced by a person early in life. Early life stress (ELS) includes maltreatment such as neglect, and interferes with the normal construction of cortical and hippocampal circuits. We hypothesized that a history of ELS contributes to persistent learning and memory dysfunction following a TBI. To explore this interaction, we modeled ELS by separating Sprague Dawley pups from their nursing mothers from post-natal days 2-14 for 3 h daily. At 2 months of age, male rats received sham surgery or mild to moderate parasagittal fluid-percussion brain injury. We found that the combination of ELS with TBI in adulthood impaired hippocampal-dependent learning, as assessed with contextual fear conditioning, the water maze task, and spatial working memory. Cortical atrophy was significantly exacerbated in TBI animals exposed to ELS compared with normal-reared TBI animals. Changes in corticosterone in response to restraint stress were prolonged in TBI animals that received ELS compared with TBI animals that were normally reared or sham animals that received ELS. Our findings indicate that ELS is a risk factor for worsened outcome after TBI, and results in persistent learning and memory deficits, worsened cortical pathology, and an exacerbation of the hormonal stress response.

Keywords: corticosterone; early life stress; fluid-percussion brain injury; learning and memory, traumatic brain injury.

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Conflict of interest statement

No competing financial interests exist.

Figures

FIG. 1.
FIG. 1.
Deficits in contextual fear conditioning after early life stress (ELS) and traumatic brain injury (TBI). TBI+ELS animals exhibited significantly less contextual fear conditioning than Sham+Ctl, Sham+ELS or TBI+Ctl animals when assessed at 24 h or 1 month after training. *p < 0.05, **p < 0.01, ***p < 0 .001 versus training; ap < 0.01 versus Sham+Ctl, Sham+ELS, TBI+Ctl; bp < 0.01 versus Sham+ELS, TBI+Ctl; cp < 0.001 versus Sham+Ctl; repeated measures two-way analysis of variance (ANOVA) with post-hoc Tukey's test. Mean ± standard error of the mean (SEM), n = 8 Sham+Ctl; n = 7 Sham+ELS; n = 6 TBI+Ctl; n = 6 TBI+ELS.
FIG. 2.
FIG. 2.
Water maze deficits after traumatic brain injury (TBI) and early life stress (ELS). (A) Water maze acquisition was not significantly impaired with either TBI or ELS treatment. (B) Retention in the water maze was assessed with a probe trial (60 sec). Time spent in the _target quadrant (Q) was significantly reduced in Sham+ELS and TBI+ELS animals compared with Sham+Ctl animals. Dotted line, chance levels.**p < 0.01, ***p < 0.001 versus other quadrants; bp < 0.001 versus TBI+Ctl; cp < 0.001 versus Sham+Ctl; repeated measures two-way analysis of variance (ANOVA) with post-hoc Tukey's test. Mean ± standard error of the mean (SEM); n = 8 Sham+Ctl; n = 7 Sham+ELS; n = 6 TBI+Ctl; n = 6 TBI+ELS.
FIG. 3.
FIG. 3.
Spatial working memory impairment in traumatic brain injured (TBI) animals. Neither TBI+Ctl nor TBI+early life stress (ELS) animals exhibited a decrease in path length to find the platform in the match trial versus the sample trial, indicating impaired working memory after TBI. **p < 0.01 versus Sham+Ctl, Sham+ELS, repeated measures two-way analysis of variance (ANOVA) with post-hoc Tukey's test. Mean ± standard error of the mean (SEM), n = 8 Sham+Ctl; n = 7 Sham+ELS; n = 6 TBI+Ctl; n = 6 TBI+ELS.
FIG. 4.
FIG. 4.
Exacerbation of cortical atrophy after traumatic brain injury (TBI) by early life stress (ELS). (A) Representative images of the parietal cortex stained with hematoxylin and eosin. Shown is bregma level -5.8 mm. Scale bar, 500 μm. (B) Cortical atrophy was significantly increased in TBI+ELS animals compared with TBI+Ctl animals. ***p < 0.001 versus Sham+Ctl, Sham+ELS ; bp < 0.01 versus TBI+Ctl. (C) Hippocampal atrophy was increased because of both TBI and ELS; however, there was no significant interaction of TBI and ELS. *p < 0.05 TBI versus Sham; ap < 0.05 ELS versus control, two-way analysis of variance (ANOVA) with post-hoc Tukey's test. Mean ± standard error of the mean (SEM); n = 8 Sham+Ctl; n = 7 Sham+ELS; n = 6 TBI+Ctl; n = 6 TBI+ELS.
FIG. 5.
FIG. 5.
Prolonged elevation of corticosterone after traumatic brain injury (TBI) and early life stress (ELS). (A) At 8 weeks post-surgery, serum was assayed for corticosterone levels. Basal and restraint-induced increases in corticosterone were similar for all treatment groups. However, after 90 min of recovery from restraint, corticosterone decreased in Sham+Ctl animals and remained elevated in TBI+Ctl and Sham+ELS animals. In contrast, corticosterone levels continued to rise in TBI+ELS animals. #p < 0.001 versus 0 min – immediately prior to restraint; *p < 0.05, ***p < 0.001 versus 30 min – immediately at end of restraint; bp < 0.01 versus Sham+ELS; cp < 0.001 vs Sham+Ctl, TBI+Ctl at 120 min – after 90 min of recovery, repeated measures two-way analysis of variance (ANOVA) with post-hoc Tukey's test. (B) At 90 min after recovery from restraint, corticosterone levels remained significantly increased because of both TBI and ELS; however, there was no interaction between TBI and ELS. Lines represent mean ± standard error of the mean (SEM). bp < 0.01 TBI versus Sham; cp < 0.001 ELS versus Ctl, two-way ANOVA with post-hoc Tukey's test. Mean ± SEM, n = 5/group.
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References

    1. Choe, M.C. (2016). The pathophysiology of concussion. Curr. Pain. Headache Rep. 20, 42. - PubMed
    1. Taylor, C.A., Bell, J.M., Breiding, M.J., and Xu, L. (2017). Traumatic brain injury–related emergency department visits, hospitalizations, and deaths - United States, 2007 and 2013. MMWR Surveill. Summ. 66, 1–16 - PMC - PubMed
    1. Peterson, A.B., Xu, L., Daugherty, J., and Breiding, M.J. (2019). Surveillance Report of Traumatic Brain Injury-Related Emergency Department Visits, Hospitalizations, and Deaths-United States, 2014. Centers for Disease Control and Prevention, United States Department of Health and Human Services: Atlanta
    1. Langlois, J.A., Rutland-Brown, W., and Thomas, K.E. (2004). Traumatic Brain Injury in the United States: Emergency Department Visits, Hospitalizations, and Deaths. Centers for Disease Control and Prevention, National Center for Injury Prevention and Control: Atlanta
    1. McCrea, M., Guskiewicz, K.M., Marshall, S.W., Barr, W., Randolph, C., Cantu, R.C., Onate, J.A., Yang, J., and Kelly, J.P. (2003). Acute effects and recovery time following concussion in collegiate football players: the NCAA concussion study. JAMA. 290, 2556–2563 - PubMed

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