Heightening of the stress response during the first weeks after a mild traumatic brain injury

doi:10.1016/j.neuroscience.2011.01.028

Neuroscience

Volume 178, 31 March 2011, Pages 147-158

https://doi.org/10.1016/j.neuroscience.2011.01.028 Get rights and content

Abstract

The effects of a mild traumatic brain injury range from white matter disruption to affective disorders. We set out to determine the response to restraint-induced stress after a mild fluid-percussion injury (FPI), an experimental model for brain injury. Hypothalamic-pituitary-adrenal (HPA) axis regulation of corticosterone (CORT) and adrenocorticotropic hormone (ACTH) was determined during the first post-injury weeks, which corresponds to the same time period when rehabilitative exercise has been shown to be ineffective after a mild FPI. Adult male rats underwent either an FPI or sham injury. Additional rats were only exposed to anesthesia. HPA regulation was evaluated by measuring the effects of dexamethasone (DEX) treatment on CORT and ACTH. Tail vein blood was collected following 30-min restraint stress, at post-injury days (PID) 1, 7 and 14, prior to (0 min) and at 30, 60, 90 and 120 min after stress onset. Results from these studies indicate that the stress response was significantly more pronounced after FPI in that CORT and ACTH restraint-induced increases were more pronounced and longer lasting compared to controls. DEX suppression of CORT and ACTH was observed in all groups, suggesting that stress hyper-responsiveness after mild FPI is not attributable to reduced sensitivity of CORT feedback regulation. The increased sensitivity to stressful events in the first two post-injury weeks after a mild FPI may have a negative impact on early rehabilitative therapies.

Research highlights

▶Mild TBI results in a dissociation of adrenocorticotropic hormone and corticosterone. ▶There is a heightened stress response in the first post injury weeks. ▶Dexamethasone suppression was observed after mild TBI.

Section snippets

Subjects

A total of 216 male Sprague–Dawley rats (mean weight: 302 g±2.46 SEM) from Charles River Breeding Labs (Hollister, CA, USA) were utilized in these experiments. Rats underwent surgery to induce either sham injury (n=81) or FPI (n=81). Additional control rats were only exposed to anesthesia (n=54). Rats were handled daily and habituated to a reversed lighting schedule (lights off: 09:00–21:00 h) commencing the week prior to experimental procedures. During the experiments, rats were single-housed

Subjects

Injured rats had a mean (±SEM) unconsciousness time of 108±5.1 s and a mean apnea time of 15±2.5 s. Four animals were deleted from the study after FPI because the severity of injury was determined to be too high (over 300 s unconsciousness) and it was the purpose of these experiments to study mild TBI. Additionally, severely injured animals have an increased risk of cardiac arrest. Although we did not measure cardiac output in our animals, by eliminating severely injured subjects we eliminated

Dissociation of ACTH and CORT was observed after a mild FPI

Basal post-injury measurements indicated that FPI elevated ACTH levels and decreased CORT. These effects on ACTH and CORT are indicative of their dissociation. The HPA response to stress initially involves hypothalamic activation of the parvocellular region of the paraventricular nucleus resulting in the release of corticotropin releasing hormone (CRH) that consequently leads to the release of ACTH from the anterior pituitary. ACTH increases normally elicit CORT release from the adrenals.

Conclusion

In summary, these experiments, in an animal model of mild TBI, indicated that there is a heightened stress response during the first two post-injury weeks. Moreover this hyper-responsiveness to stress is evident when basal levels of ACTH and CORT are similar to those of controls. It should be noted that the time windows utilized in the animal models of TBI are most likely different from those found in humans. Specific time windows are more achievable in animal models of TBI because there is

Acknowledgments

This study was supported by NINDS award NS6190 (GSG) and the UCLA Brain Injury Research Center. We would also wish to thank David L. McArthur, PhD. for his statistical advice and David Garfinkel for his excellent technical help.

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Neurodegeneration, Neuroprotection, and Disease-Oriented NeuroscienceResearch PaperHeightening of the stress response during the first weeks after a mild traumatic brain injury

Abstract

Research highlights

Section snippets

Subjects

Subjects

Dissociation of ACTH and CORT was observed after a mild FPI

Conclusion

Acknowledgments

Trends Endocrinol Metab

Eur J Pharmacol

Brain Res

Neuroscience

Pharmacol Biochem Behav

Brain Res

Prog Neuropsychopharmacol Biol Psychiatry

Brain Res

Brain Res

Neuroscience

Chin J Traumatol

Neuroendocrine dysfunction in the acute phase of traumatic brain injury

Clin Endocrinol (Oxf)

Anterior pituitary dysfunction in survivors of traumatic brain injury

J Clin Endocrinol Metab

Neurobehavioral consequences of traumatic brain injury

Mt Sinai J Med

Synaptic strength modulation after cortical trauma: a role in epileptogenesis

J Neurosci

Bench to bedside: evidence for brain injury after concussion—looking beyond the computed tomography scan

Acad Emerg Med

Clinical review 113: hypopituitarism secondary to head trauma

J Clin Endocrinol Metab

Rates of major depressive disorder and clinical outcomes following traumatic brain injury

JAMA

Occurrence of pituitary dysfunction following traumatic brain injury

J Neurotrauma

Neuroendocrine responses following graded traumatic brain injury in male adults

Brain Inj

Acute secondary adrenal insufficiency after traumatic brain injury: a prospective study

Crit Care Med

Activation of the adrenocortical axis by surgical stress: involvement of central norepinephrine and interleukin-1

Neuroimmunomodulation

Emergency department visits, hospitalizations and deaths 2002–2006

Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs low CRH/NE states

Mol Psychiatry

Time window for voluntary exercise-induced increases in hippocampal neuroplasticity molecules after traumatic brain injury is severity dependent

J Neurotrauma

Alterations in BDNF and synapsin I within the occipital cortex and hippocampus after mild traumatic brain injury in the developing rat: reflections of injury-induced neuroplasticity

J Neurotrauma

The hypothalamo-pituitary-adrenal axis response to experimental traumatic brain injury

J Neurotrauma

Evolution of post-traumatic neurodegeneration after controlled cortical impact traumatic brain injury in mice and rats as assessed by the de Olmos silver and fluorojade staining methods

J Neurotrauma

Gluco- and mineralocorticoid receptor-mediated regulation of neurotrophic factor gene expression in the dorsal hippocampus and the neocortex of the rat

Eur J Neurosci

Corticosterone actions on the hippocampal brain-derived neurotrophic factor expression are mediated by exon IV promoter

J Neuroendocrinol

Traumatic brain injury-induced changes in gene expression and functional activity of mitochondrial cytochrome C oxidase

J Neurotrauma

Change in circulating blood volume following craniotomy

J Neurosurg

Differential responsivity of the hypothalamic-pituitary-adrenal axis to glucocorticoid negative-feedback and corticotropin releasing hormone in rats undergoing morphine withdrawal: possible mechanisms involved in facilitated and attenuated stress responses

J Neuroendocrinol

The hypothalamic-pituitary-adrenal axis in critical illness

AACN Clin Issues

[The hypothalamic pituitary adrenal axis, glucocorticoid receptor function and relevance to depression]

Rev Bras Psiquiatr

Neurodegeneration, Neuroprotection, and Disease-Oriented Neuroscience
Research Paper
Heightening of the stress response during the first weeks after a mild traumatic brain injury