Regional hippocampal alteration associated with cognitive deficit following experimental brain injury: A systems, network and cellular evaluation

Witgen, Brent M.; Lifshitz, Jonathan; Smith, Michael L.; Schwarzbach, Elizabeth; Liang, Sophie Hsin-Yi; Grady, M. Sean; Cohen, Akiva S.

doi:10.1016/j.neuroscience.2005.01.052

Cited by 196 publications

(230 citation statements)

References 84 publications

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“…Accordingly, there are consistent, quantifiable focal and diffuse histopathologies that are all potential therapeutic targets (Dietrich et al, 1994, Bramlett et al, 1997, Ciallella et al, 2002, Grady et al, 2003, Suzuki et al, 2003, Suzuki et al, 2004, Witgen et al, 2005. In our studies, we found that rolipram, a selective PDE IV antagonist, improved histopathology at multiple levels.…”

Section: Discussionsupporting

confidence: 63%

“…The parasagittal FPI model results in stereotypical neuronal death in the parietal cortex overlying the cortical contusion and in the CA3 region of the hippocampus (Grady et al, 2003, Witgen et al, 2005. Treatment of rolipram during TBI and for 3 days following moderate FPI improved neuronal survival in both the parietal cortex (Fig.…”

Section: Resultsmentioning

confidence: 93%

“…We chose to pre-treat animals with rolipram to target the acute, rapid inflammatory signaling events initiated by trauma (Kinoshita et al, 2002. Animals were assessed for histopathology at 3 days after TBI because there are reproducible, quantifiable histopathologies at this time point (Dietrich et al, 1994, Bramlett et al, 1997, Suzuki et al, 2003, Suzuki et al, 2004 The parasagittal FPI model results in stereotypical neuronal death in the parietal cortex overlying the cortical contusion and in the CA3 region of the hippocampus (Grady et al, 2003, Witgen et al, 2005. Treatment of rolipram during TBI and for 3 days following moderate FPI improved neuronal survival in both the parietal cortex (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Modulation of the cAMP signaling pathway after traumatic brain injury

Atkins

Oliva

Alonso

et al. 2007

Experimental Neurology

136

151

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Traumatic brain injury (TBI) results in both focal and diffuse brain pathologies that are exacerbated by the inflammatory response and progress from hours to days after the initial injury. Using a clinically relevant model of TBI, the parasagittal fluid-percussion brain injury (FPI) model, we found injury-induced impairments in the cyclic AMP (cAMP) signaling pathway. Levels of cAMP were depressed in the ipsilateral parietal cortex and hippocampus, as well as activation of its downstream target, protein kinase A, from 15 min to 48 hr after moderate FPI. To determine if preventing hydrolysis of cAMP by administration of a phosphodiesterase (PDE) IV inhibitor would improve outcome after TBI, we treated animals intraperitoneally with rolipram (0.3 or 3.0 mg/kg) 30 min prior to TBI, and then once per day for three days. Rolipram treatment restored cAMP to sham levels and significantly reduced cortical contusion volume and improved neuronal cell survival in the parietal cortex and CA3 region of the hippocampus. Traumatic axonal injury, characterized by β-amyloid precursor protein deposits in the external capsule, was also significantly reduced in rolipramtreated animals. Furthermore, levels of the pro-inflammatory cytokines, interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), were significantly decreased with rolipram treatment. These results demonstrate that the cAMP-PKA signaling cascade is downregulated after TBI, and that treatment with a PDE IV inhibitor improves histopathological outcome and decreases inflammation after TBI. Keywordscamp; Fluid-percussion; Inflammation; Interleukin-1β; PKA; Phosphodiesterase; Rolipram; TNF-α; Traumatic brain injury; TBI Traumatic brain injury (TBI) is a prevalent, debilitating health problem, occurring in 1.4 million people each year and disabling 5 million people in the United States (Langlois et al., 2004). The subsequent progressive injury after brain trauma develops from hours to days after the initiating insult, providing an accessible time window for pharmacological therapies. Despite Address correspondence to: W. Dalton Dietrich, Scientific Director, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, P.O. Box 016960, (R-48), Miami, FL 33101, E-mail: ddietrich@miami.edu, Phone: 305-243-2297, Fax: 305-243-3207. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Brain trauma results in contusion formation, neuronal apoptosis, and axonal tract damage. These pathologies are worsened by the inflammatory cascade set into motion by the initial injury (Morganti-Kossmann et al., 2002. Two pro-i...

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Section: Discussionsupporting

confidence: 63%

Section: Resultsmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

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Modulation of the cAMP signaling pathway after traumatic brain injury

Atkins

Oliva

Alonso

et al. 2007

Experimental Neurology

136

151

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“…Stereological reports have demonstrated a significant non-progressive loss of neurons throughout the hippocampus ipsilateral to unilateral FPI [12,28,87,88], and contralateral neuronal damage can be detected by fluorojade-positive staining [36,75]. Systematic neuropathology within the amygdala has yet to be reported, however qualitative histology demonstrates no overt pathology [38].…”

Section: Introductionmentioning

confidence: 99%

“…By varying the temporal spacing of the training, the brain injury and the testing, the effects of TBI on acquisition, consolidation and recall of a conditioned fear cognitive task could be evaluated. Since, brain-injured mice may be incapable of recalling an association conditioned immediately prior to brain injury due to retrograde amnesia [88], the present design explores anterograde cognitive function in the injured brain. Furthermore, quantitative stereological analysis of the basolateral amygdala complex and central nucleus were undertaken, since they serve the anatomical basis for amygdala-dependent conditioned fear [59,76].…”

Section: Introductionmentioning

confidence: 99%

Acute cognitive impairment after lateral fluid percussion brain injury recovers by 1 month: Evaluation by conditioned fear response

Lifshitz

Witgen

Grady

2007

Behavioural Brain Research

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Conditioned fear associates a contextual environment and cue stimulus to a foot shock in a single training trial, where fear expressed to the trained context or cue indicates cognitive performance. Lesion, aspiration or inactivation of the hippocampus and amygdala impair conditioned fear to the trained context and cue, respectively. Moreover, only bilateral experimental manipulations, in contrast to unilateral, abolish cognitive performance.In a model of unilateral brain injury, we sought to test whether a single lateral fluid percussion brain injury impairs cognitive performance in conditioned fear. Brain-injured mice were evaluated for anterograde cognitive deficits, with the hypothesis that acute injury-induced impairments improve over time. Male C57BL/6J mice were brain-injured, trained at five or 27 days post-injury, and tested 48 hours later for recall of the association between the conditioned stimuli (trained context or cue) and the unconditioned stimulus (foot shock) by quantifying fear-associated freezing behavior. A significant anterograde hippocampal-dependent cognitive deficit was observed at seven days in brain-injured compared to sham. Cued fear conditioning could not detect amygdala-dependent cognitive deficits after injury and stereological estimation of amygdala neuron number corroborated this finding. The absence of injury-related freezing in a novel context substantiated injury-induced hippocampal-dependent cognitive dysfunction, rather than generalized fear. Variations in the training and testing paradigms demonstrated a cognitive deficit in consolidation, rather than acquisition or recall. By one month post-injury, cognitive function recovered in brain-injured mice. Hence, the acute injury-induced cognitive impairment may persist while transient pathophysiological sequelae are underway, and improve as global dysfunction subsides.

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Inhibitory neuronal changes following a mixed diffuse‐focal model of traumatic brain injury

Carron

Sun

Shultz

et al. 2019

J of Comparative Neurology

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Traumatic brain injury (TBI) can result in excitation: inhibition imbalance, as well as a range of chronic neurological deficits. However, how TBI affects different interneurons, and how this relates to behavioral abnormalities, remains poorly understood. This study examined the effects of a mixed diffuse‐focal model of TBI, the lateral fluid percussion injury (LFPI), on interneurons, 8 weeks post‐TBI in rats. Brains were labeled with antibodies against calbindin, parvalbumin, calretinin, neuropeptide Y, and somatostatin, and the number of interneurons were assessed in the cortex and hippocampus following LFPI. LFPI caused a reduction in the numbers of interneurons mediating both perisomatic and dendritic inhibition in the somatosensory cortex. In hippocampus, there were heterogenous changes in the number of interneurons while motor cortex, showed no obvious loss in any of the subsets of interneurons after TBI. In parallel to the investigations of changes in the number of interneurons, we also investigated the long‐term behavioral consequences of LFPI. Behaviorally, rats given an LFPI displayed transient reduction in performance in motor tasks and were significantly impaired in reversal learning in the water maze task post‐TBI. We also report here progressive neurodegeneration in cortex and hippocampus indicated by Fluoro‐Jade C in the different brain areas examined after injury. Our findings suggest differential vulnerability of inhibitory neurons to LFPI in the different brain areas examined after injury. These data will aid in evaluation of new treatments for TBI and help target specific neuronal subtypes as a function of injury time and type.

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Regional hippocampal alteration associated with cognitive deficit following experimental brain injury: A systems, network and cellular evaluation

Cited by 196 publications

References 84 publications

Modulation of the cAMP signaling pathway after traumatic brain injury

Modulation of the cAMP signaling pathway after traumatic brain injury

Acute cognitive impairment after lateral fluid percussion brain injury recovers by 1 month: Evaluation by conditioned fear response

Inhibitory neuronal changes following a mixed diffuse‐focal model of traumatic brain injury

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