Isolated spinal cord contusion in rats induces chronic brain neuroinflammation, neurodegeneration, and cognitive impairment

Wu, Junfang; Stoica, Bogdan A.; Luo, Tao; Sabirzhanov, Boris; Zhao, Zhihong; Guanciale, Kelsey; Nayar, Suresh K.; Foss, Catherine A.; Pomper, Martin G.; Faden, Alan I.

doi:10.4161/cc.29420

Cited by 91 publications

(112 citation statements)

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“…[17][18][19][20] However, a direct relationship between injury severity and associated cognitive deficits or depression has not been established. Importantly, for an SCI model, the characterization of behaviors for cognition and depression should not depend on motor function.…”

Section: Discussionmentioning

confidence: 99%

“…65 Previous in vitro studies indicate that oligodendrocytes exposed to inflammatory proteins IFN-c exhibit features of ER stress, 66 representing yet another link between ER stress and neuroinflammation. Previously, we and others 18,19,21,41 have shown significant elevation of pro-inflammatory cytokines in the hippocampi after SCI, including tumor necrosis factor (TNF)-a, interleukin (IL) 1-a, inducible nitric oxide synthase, CCL2/3. Thus, SCI-mediated chronic neuroinflammatory response in the brain may contribute to ER stress.…”

Section: Fig 5 the Hippocampal Neurogenesis Is Impaired Following Smentioning

confidence: 99%

“…49,53 More recently, CCL21 signaling was found increased in neuronal cell bodies and parenchyma within both the hippocampus and cortex at 7 days after SCI. 19 Here, we examined CCL21 immunoreactivity in key brain regions from sham, mild, moderate, and severe SCI mice at 16 weeks post-injury. Quantification of pixel intensity for CCL21 revealed significant increases in the cortex, hippocampus, and thalamus in all injured groups (Fig.…”

Section: Ccl21 Accumulation In the Brain Following Scimentioning

confidence: 99%

“…36 Chemokines CCL2/CCL3 are chronically expressed not only in thalamus, but also in hippocampus (CA3 and DG sub-regions), and periaqueductal gray matter after severe SCI. 41 Our recent autoradiography studies 19 in rats after SCI, using a new TSPO ligand […”

Section: Disrupted Brain Neurogenesis/er Stress Aftermentioning

confidence: 99%

“…38,39 Increased inflammation in the brain after SCI has been reported not only in pain regulatory areas, such as the brainstem and thalamus, but also in the hippocampus and cerebral cortex. 18,19,21,36,40,41 Moreover, SCI significantly increases M1-like microglial activation genes in the hippocampus, along with changes in M2a-like and M2c-like markers.…”

Section: Introductionmentioning

confidence: 99%

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Endoplasmic Reticulum Stress and Disrupted Neurogenesis in the Brain Are Associated with Cognitive Impairment and Depressive-Like Behavior after Spinal Cord Injury

Zhao

Kumar

et al. 2016

Journal of Neurotrauma

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Clinical and experimental studies show that spinal cord injury (SCI) can cause cognitive impairment and depression that can significantly impact outcomes. Thus, identifying mechanisms responsible for these less well-examined, important SCI consequences may provide targets for more effective therapeutic intervention. To determine whether cognitive and depressive-like changes correlate with injury severity, we exposed mice to sham, mild, moderate, or severe SCI using the Infinite Horizon Spinal Cord Impactor and evaluated performance on a variety of neurobehavioral tests that are less dependent on locomotion. Cognitive impairment in Y-maze, novel objective recognition, and step-down fear conditioning tasks were increased in moderate-and severe-injury mice that also displayed depressive-like behavior as quantified in the sucrose preference, tail suspension, and forced swim tests. Bromo-deoxyuridine incorporation with immunohistochemistry revealed that SCI led to a long-term reduction in the number of newly-generated immature neurons in the hippocampal dentate gyrus, accompanied by evidence of greater neuronal endoplasmic reticulum (ER) stress. Stereological analysis demonstrated that moderate/severe SCI reduced neuronal survival and increased the number of activated microglia chronically in the cerebral cortex and hippocampus. The potent microglial activator cysteine-cysteine chemokine ligand 21 (CCL21) was elevated in the brain sites after SCI in association with increased microglial activation. These findings indicate that SCI causes chronic neuroinflammation that contributes to neuronal loss, impaired hippocampal neurogenesis and increased neuronal ER stress in important brain regions associated with cognitive decline and physiological depression. Accumulation of CCL21 in brain may subserve a pathophysiological role in cognitive changes and depression after SCI.

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Section: Discussionmentioning

confidence: 99%

Section: Fig 5 the Hippocampal Neurogenesis Is Impaired Following Smentioning

confidence: 99%

Section: Ccl21 Accumulation In the Brain Following Scimentioning

confidence: 99%

Section: Disrupted Brain Neurogenesis/er Stress Aftermentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Endoplasmic Reticulum Stress and Disrupted Neurogenesis in the Brain Are Associated with Cognitive Impairment and Depressive-Like Behavior after Spinal Cord Injury

Zhao

Kumar

et al. 2016

Journal of Neurotrauma

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105

100

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Metabolomics analysis of the hippocampus in a rat model of traumatic brain injury during the acute phase

et al. 2020

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Background: Traumatic brain injury (TBI) has increased in rank among traumatic injuries worldwide. Traumatic brain injury is a serious obstacle given that its complex pathology represents a long-term process. Recently, systems biology strategies such as metabolomics to investigate the multifactorial nature of TBI have facilitated attempts to find biomarkers and probe molecular pathways for its diagnosis and therapy. Methods:This study included a group of 20 rats with controlled cortical impact and a group of 20 sham rats. We utilized mNSS tests to investigate neurological metabolic impairments on day 1 and day 3. Furthermore, we applied metabolomics and bioinformatics to determine the metabolic perturbation caused by TBI during the acute period in the hippocampus tissue of controlled cortical impact (CCI) rats. Notably, TBI-protein-metabolite subnetworks identified from a database were assessed for associations between metabolites and TBI by the dysregulation of related enzymes and transporters. Results:Our results identified 7 and 8 biomarkers on day 1 and day 3, respectively.Additionally, related pathway disorders showed effects on arginine and proline metabolism as well as taurine and hypotaurine metabolism on day 3 in acute TBI.Furthermore, according to metabolite-protein database searches, 25 metaboliteprotein pairs were established as causally associated with TBI. Further, bioinformation indicated that these TBI-associated proteins mainly take part in 5′-nucleotidase activity and carboxylic acid transmembrane transport. In addition, interweaved networks were constructed to show that the development of TBI might be affected by metabolite-related proteins and their protein pathways. Conclusion:The overall results show that acute TBI is susceptible to metabolic disorders, and the joint metabolite-protein network analysis provides a favorable prediction of TBI pathogenesis mechanisms in the brain. The signatures in the hippocampus might be promising for the development of biomarkers and pathways relevant to acute TBI and could further guide testable predictions of the underlying mechanism of TBI.

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Neuropathic pain following traumatic spinal cord injury: Models, measurement, and mechanisms

Kramer

Minhas

Jutzeler

et al. 2016

J of Neuroscience Research

103

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Neuropathic pain following spinal cord injury (SCI) is notoriously difficult to treat and is a high priority for many in the SCI population. Resolving this issue requires animal models fidelic to the clinical situation in terms of injury mechanism and pain phenotype. This Review discusses the means by which neuropathic pain has been induced and measured in experimental SCI and compares these with human outcomes, showing that there is a substantial disconnection between experimental investigations and clinical findings in a number of features. Clinical injury level is predominantly cervical, whereas injury in the laboratory is modeled mainly at the thoracic cord. Neuropathic pain is primarily spontaneous or tonic in people with SCI (with a relatively smaller incidence of allodynia), but measures of evoked responses (to thermal and mechanical stimuli) are almost exclusively used in animals. There is even the question of whether pain per se has been under investigation in most experimental SCI studies rather than simply enhanced reflex activity with no affective component. This Review also summarizes some of the problems related to clinical assessment of neuropathic pain and how advanced imaging techniques may circumvent a lack of patient/clinician objectivity and discusses possible etiologies of neuropathic pain following SCI based on evidence from both clinical studies and animal models, with examples of cellular and molecular changes drawn from the entire neuraxis from primary afferent terminals to cortical sensory and affective centers. © 2016 Wiley Periodicals, Inc.

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Isolated spinal cord contusion in rats induces chronic brain neuroinflammation, neurodegeneration, and cognitive impairment

Cited by 91 publications

References 64 publications

Endoplasmic Reticulum Stress and Disrupted Neurogenesis in the Brain Are Associated with Cognitive Impairment and Depressive-Like Behavior after Spinal Cord Injury

Endoplasmic Reticulum Stress and Disrupted Neurogenesis in the Brain Are Associated with Cognitive Impairment and Depressive-Like Behavior after Spinal Cord Injury

Metabolomics analysis of the hippocampus in a rat model of traumatic brain injury during the acute phase

Neuropathic pain following traumatic spinal cord injury: Models, measurement, and mechanisms

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