Effects of Traumatic Brain Injury of Different Severities on Emotional, Cognitive, and Oxidative Stress-Related Parameters in Mice

Centro de Neurociências Aplicadas, Hospital Universitário, Universidade Federal de Santa Catarina, Florianópolis, Brazil.
Journal of neurotrauma (Impact Factor: 3.71). 10/2010; 27(10):1883-93. DOI: 10.1089/neu.2010.1318
Source: PubMed


Cognitive deficits and psychiatric disorders are significant sequelae of traumatic brain injury (TBI). Animal models have been widely employed in TBI research, but few studies have addressed the effects of experimental TBI of different severities on emotional and cognitive parameters. In this study, mice were subjected to weight-drop TBI to induce mild, intermediate, or severe TBI. After neurological assessment, the mice recovered for 10 days, and were then subjected to a battery of behavioral tests, which included open-field, elevated plus-maze, forced swimming, tail suspension, and step-down inhibitory avoidance tests. Oxidative stress-related parameters (nonprotein thiols [NPSH], glutathione peroxidase [GPx], glutathione reductase [GR], and thiobarbituric acid reactive species [TBARS]) were quantified in the cortex and hippocampus at 2 and 24 h and 14 days after TBI, and histopathological analysis was performed 15 days after TBI. Mice subjected to mild TBI showed increased anxiety and depressive-like behaviors, while intermediate and severe TBI induced robust memory deficits. The severe TBI group also displayed increased locomotor activity. Intermediate and severe TBI caused extensive macroscopic and microscopic brain damage, while mild TBI typically had no histological abnormalities. Moreover, a significant increase in TBARS in the ipsilateral cortex and GPx in the ipsilateral hippocampus was observed at 24 h and 14 days, respectively, following intermediate TBI. The current experimental TBI model induced emotional and cognitive changes comparable to sequelae seen in human TBI, and it might therefore represent a useful approach to the study of mechanisms of and new treatments for TBI and related disorders.

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Available from: Daniel Rial, Mar 16, 2015
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    • "In mice, no increased anxiety was reported in elevated plus maze at either 1, 2 or 3.5 weeks after weight drop in several studies (22, 23, 67), but was detected at 11 days in another (68). Depression was detected in mice at 7 days using the Porsolt swim test (69), and at 3 and 13 days using the tail suspension test (68, 70). Some studies in mice reported heightened fearfulness in passive avoidance tasks in the month after weight drop TBI (22), while others reported reduced fear learning (69), and others no change (23, 70). "
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    ABSTRACT: Emotional disorders are a common outcome from mild traumatic brain injury (TBI) in humans, but their pathophysiological basis is poorly understood. We have developed a mouse model of closed-head blast injury using an air pressure wave delivered to a small area on one side of the cranium, to create mild TBI. We found that 20-psi blasts in 3-month-old C57BL/6 male mice yielded no obvious behavioral or histological evidence of brain injury, while 25-40 psi blasts produced transient anxiety in an open field arena but little histological evidence of brain damage. By contrast, 50-60 psi blasts resulted in anxiety-like behavior in an open field arena that became more evident with time after blast. In additional behavioral tests conducted 2-8 weeks after blast, 50-60 psi mice also demonstrated increased acoustic startle, perseverance of learned fear, and enhanced contextual fear, as well as depression-like behavior and diminished prepulse inhibition. We found no evident cerebral pathology, but did observe scattered axonal degeneration in brain sections from 50 to 60 psi mice 3-8 weeks after blast. Thus, the TBI caused by single 50-60 psi blasts in mice exhibits the minimal neuronal loss coupled to "diffuse" axonal injury characteristic of human mild TBI. A reduction in the abundance of a subpopulation of excitatory projection neurons in basolateral amygdala enriched in Thy1 was, however, observed. The reported link of this neuronal population to fear suppression suggests their damage by mild TBI may contribute to the heightened anxiety and fearfulness observed after blast in our mice. Our overpressure air blast model of concussion in mice will enable further studies of the mechanisms underlying the diverse emotional deficits seen after mild TBI.
    Full-text · Article · Jan 2014 · Frontiers in Neurology
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    • "Schwarzbold and colleagues (84) found that mice 11 days after a TBI induced by a 10-g weight dropped on the left parietal region (from a height of 120 cm) exhibited a significant decrease in entries into the open arms, and spent less time in the open arms (anxiety-like behavior) compared to sham controls and to mice with TBI induced by 12.5 and 15 g weight dropped on the same brain region, suggesting that a mild TBI, but not more severe injuries, may result in an elevated anxiety response. On the other hand, Pandey and colleagues (92) found that 14 days after a mild TBI (400 g weight, 10 mm diameter, dropped from a height of 1 m on the exposed skull, mid-distance between lambda and bregma sutures), rats exhibited a significant increase in both percentage of open-to-total arm entries and percentage of total time spent in the open arms when compared with rats that underwent sham surgery. "
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    ABSTRACT: Each year in the US, ∼1.5 million people sustain a traumatic brain injury (TBI). Victims of TBI can suffer from chronic post-TBI symptoms, such as sensory and motor deficits, cognitive impairments including problems with memory, learning, and attention, and neuropsychiatric symptoms such as depression, anxiety, irritability, aggression, and suicidal rumination. Although partially associated with the site and severity of injury, the biological mechanisms associated with many of these symptoms - and why some patients experience differing assortments of persistent maladies - are largely unknown. The use of animal models is a promising strategy for elucidation of the mechanisms of impairment and treatment, and learning, memory, sensory, and motor tests have widespread utility in rodent models of TBI and psychopharmacology. Comparatively, behavioral tests for the evaluation of neuropsychiatric symptomatology are rarely employed in animal models of TBI and, as determined in this review, the results have been inconsistent. Animal behavioral studies contribute to the understanding of the biological mechanisms by which TBI is associated with neurobehavioral symptoms and offer a powerful means for pre-clinical treatment validation. Therefore, further exploration of the utility of animal behavioral tests for the study of injury mechanisms and therapeutic strategies for the alleviation of emotional symptoms are relevant and essential.
    Full-text · Article · Oct 2013 · Frontiers in Neurology
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    • "Our findings of increased immobility in the tail suspension test after rcTBI were consistent with a study of weight-drop TBI in Swiss mice, where the least severe injury resulted in increased immobility in the tail suspension test [49]. Likewise, a model of controlled cortical impact (CCI) TBI in mice also found increased immobility time in the tail suspension test, though in this study only the more severe injuries were associated with significant increases in immobility time [50]. "
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    ABSTRACT: The debilitating effects of repetitive concussive traumatic brain injury (rcTBI) have been increasingly recognized in both military and civilian populations. rcTBI may result in significant neurological, cognitive, and affective sequelae, and is often followed by physical and/or psychological post-injury stressors that may exacerbate the effects of the injury and prolong the recovery period for injured patients. However, the consequences of post-injury stressors and their subsequent effects on social and emotional behavior in the context of rcTBI have been relatively little studied in animal models. Here, we use a mouse model of rcTBI with two closed-skull blunt impacts 24 hours apart and social and emotional behavior testing to examine the consequences of a stressor (foot shock fear conditioning) following brain injury (rcTBI). rcTBI alone did not affect cued or contextual fear conditioning or extinction compared to uninjured sham animals. In the sucrose preference test, rcTBI animals had decreased preference for sucrose, an anhedonia-like behavior, regardless of whether they experienced foot shock stress or were non-shocked controls. However, rcTBI and post-injury foot shock stress had synergistic effects in tests of social recognition and depression-like behavior. In the social recognition test, animals with both injury and shock were more impaired than either non-shocked injured mice or shocked but uninjured mice. In the tail suspension test, injured mice had increased depression-like behavior compared with uninjured mice, and shock stress worsened the depression-like behavior only in the injured mice with no effect in the uninjured mice. These results provide a model of subtle emotional behavioral deficits after combined concussive brain injury and stress, and may provide a platform for testing treatment and prevention strategies for social behavior deficits and mood disorders that are tailored to patients with traumatic brain injury.
    Preview · Article · Sep 2013 · PLoS ONE
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