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      Stress and Traumatic Brain Injury: A Behavioral, Proteomics, and Histological Study

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          Psychological stress and traumatic brain injury (TBI) can both result in lasting neurobehavioral abnormalities. Post-traumatic stress disorder and blast induced TBI (bTBI) have become the most significant health issues in current military conflicts. Importantly, military bTBI virtually never occurs without stress. In this experiment, we assessed anxiety and spatial memory of rats at different time points after repeated exposure to stress alone or in combination with a single mild blast. At 2 months after injury or sham we analyzed the serum, prefrontal cortex (PFC), and hippocampus (HC) of all animals by proteomics and immunohistochemistry. Stressed sham animals showed an early increase in anxiety but no memory impairment at any measured time point. They had elevated levels of serum corticosterone (CORT) and hippocampal IL-6 but no other cellular or protein changes. Stressed injured animals had increased anxiety that returned to normal at 2 months and significant spatial memory impairment that lasted up to 2 months. They had elevated serum levels of CORT, CK-BB, NF-H, NSE, GFAP, and VEGF. Moreover, all of the measured protein markers were elevated in the HC and the PFC; rats had an increased number of TUNEL-positive cells in the HC and elevated GFAP and Iba1 immunoreactivity in the HC and the PFC. Our findings suggest that exposure to repeated stress alone causes a transient increase in anxiety and no significant memory impairment or cellular and molecular changes. In contrast, repeated stress and blast results in lasting behavioral, molecular, and cellular abnormalities characterized by memory impairment, neuronal and glial cell loss, inflammation, and gliosis. These findings may have implications in the development of diagnostic and therapeutic measures for conditions caused by stress or a combination of stress and bTBI.

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          Most cited references 77

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          Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo.

          Vascular endothelial growth factor (VEGF) is an angiogenic protein with neurotrophic and neuroprotective effects. Because VEGF promotes the proliferation of vascular endothelial cells, we examined the possibility that it also stimulates the proliferation of neuronal precursors in murine cerebral cortical cultures and in adult rat brain in vivo. VEGF (>10 ng/ml) stimulated 5-bromo-2'-deoxyuridine (BrdUrd) incorporation into cells that expressed immature neuronal marker proteins and increased cell number in cultures by 20-30%. Cultured cells labeled by BrdUrd expressed VEGFR2/Flk-1, but not VEGFR1/Flt-1 receptors, and the effect of VEGF was blocked by the VEGFR2/Flk-1 receptor tyrosine kinase inhibitor SU1498. Intracerebroventricular administration of VEGF into rat brain increased BrdUrd labeling of cells in the subventricular zone (SVZ) and the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG), where VEGFR2/Flk-1 was colocalized with the immature neuronal marker, doublecortin (Dcx). The increase in BrdUrd labeling after the administration of VEGF was caused by an increase in cell proliferation, rather than a decrease in cell death, because VEGF did not reduce caspase-3 cleavage in SVZ or SGZ. Cells labeled with BrdUrd after VEGF treatment in vivo include immature and mature neurons, astroglia, and endothelial cells. These findings implicate the angiogenesis factor VEGF in neurogenesis as well.
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            Regional dissociations within the hippocampus--memory and anxiety.

            The amnestic effects of hippocampal lesions are well documented, leading to numerous memory-based theories of hippocampal function. It is debatable, however, whether any one of these theories can satisfactorily account for all the consequences of hippocampal damage: Hippocampal lesions also result in behavioural disinhibition and reduced anxiety. A growing number of studies now suggest that these diverse behavioural effects may be associated with different hippocampal subregions. There is evidence for at least two distinct functional domains, although recent neuroanatomical studies suggest this may be an underestimate. Selective lesion studies show that the hippocampus is functionally subdivided along the septotemporal axis into dorsal and ventral regions, each associated with a distinct set of behaviours. Dorsal hippocampus has a preferential role in certain forms of learning and memory, notably spatial learning, but ventral hippocampus may have a preferential role in brain processes associated with anxiety-related behaviours. The latter's role in emotional processing is also distinct from that of the amygdala, which is associated specifically with fear. Gray and McNaughton's theory can in principle incorporate these apparently distinct hippocampal functions, and provides a plausible unitary account for the multiple facets of hippocampal function.
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              A meta-analysis of structural brain abnormalities in PTSD.

              This series of meta-analyses examined structural abnormalities of the hippocampus and other brain regions in persons with PTSD compared to trauma-exposed and non-exposed control groups. The findings were significantly smaller hippocampal volumes in persons with PTSD compared to controls with and without trauma exposure, but group differences were moderated by MRI methodology, PTSD severity, medication, age and gender. Trauma-exposed persons without PTSD also showed significantly smaller bilateral hippocampal compared to non-exposed controls. Meta-analyses also found significantly smaller left amygdala volumes in adults with PTSD compared to both healthy and trauma-exposed controls, and significantly smaller anterior cingulate cortex compared to trauma-exposed controls. Pediatric samples with PTSD exhibited significantly smaller corpus callosum and frontal lobe volumes compared to controls, but there were no group differences in hippocampal volume. The overall findings suggested a dimensional, developmental psychopathology systems model in which: (1) hippocampal volumetric differences covary with PTSD severity; (2) hippocampal volumetric differences do not become apparent until adulthood; and (3) PTSD is associated with abnormalities in multiple frontal-limbic system structures.

                Author and article information

                Front Neurol
                Front. Neur.
                Frontiers in Neurology
                Frontiers Research Foundation
                07 March 2011
                : 2
                1Department of Anatomy, Physiology and Genetics, School of Medicine, Uniformed Services University Bethesda, MD, USA
                2Division of Military Casualty Research, Walter Reed Army Institute of Research Silver Spring, MD, USA
                Author notes

                Edited by: Marten Risling, Karolinska Institutet, Sweden

                Reviewed by: Linda Noble, University of California at San Francisco, USA; Robert Vink, University of Adelaide, Australia

                *Correspondence: Denes V. Agoston, Department of Anatomy, Physiology and Genetics, School of Medicine, Uniformed Services University, 4301 Jones Bridge Road, Bethesda, MD 20814, USA. e-mail: vagoston@ 123456usuhs.edu
                Sook-Kyung C. Kwon and Erzsebet Kovesdi have contributed equally.

                This article was submitted to Frontiers in Neurotrauma, a specialty of Frontiers in Neurology.

                Copyright © 2011 Kwon, Kovesdi, Gyorgy, Wingo, Kamnaksh, Walker, Long and Agoston.

                This is an open-access article subject to an exclusive license agreement between the authors and Frontiers Media SA, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are credited.

                Page count
                Figures: 11, Tables: 0, Equations: 0, References: 90, Pages: 14, Words: 10215
                Original Research


                stress, gliosis, inflammation, blast traumatic brain injury, anxiety, neurogenesis, memory


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