Enduring deficits in memory and neuronal pathology after blast-induced traumatic brain injury

Sajja, Venkata Siva Sai Sujith; Hubbard, W. B.; Hall, Christina; Ghoddoussi, Farhad; Galloway, Matthew P.; VandeVord, Pamela J.

doi:10.1038/srep15075

Cited by 52 publications

(65 citation statements)

References 47 publications

(131 reference statements)

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“…We were somewhat surprised that the impairment in spatial object recognition did not worsen with increasing blast severity, though, and additional studies to explore how this impairment is affected by the direction and complexity of the blast wave is warranted. These additional studies may also resolve past work that shows blast exposure can differentially affect hippocampal-dependent behaviors (Budde et al, 2013; Sajja et al, 2015; Tompkins et al, 2013; Tweedie et al, 2013), a discrepancy that can be explained by characteristics of the blast loading.…”

Section: Discussionmentioning

confidence: 77%

Primary blast injury causes cognitive impairments and hippocampal circuit alterations

Beamer¹,

Tummala²,

Gullotti³

et al. 2016

Experimental Neurology

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Blast-induced traumatic brain injury (bTBI) and its long term consequences are a major health concern among veterans. Despite recent work enhancing our knowledge about bTBI, very little is known about the contribution of the blast wave alone to the observed sequelae. Herein, we isolated its contribution in a mouse model by constraining the animals' heads during exposure to a shockwave (primary blast). Our results show that exposure to primary blast alone results in changes in hippocampus-dependent behaviors that correspond with electro-physiological changes in area CA1 and are accompanied by reactive gliosis. Specifically, five days after exposure, behavior in an open field and performance in a spatial object recognition (SOR) task were significantly different from sham. Network electrophysiology, also performed five days after injury, demonstrated a significant decrease in excitability and increase in inhibitory tone. Immunohistochemistry for GFAP and Iba1 performed ten days after injury showed a significant increase in staining. Interestingly, a threefold increase in the impulse of the primary blast wave did not exacerbate these measures. However, we observed a significant reduction in the contribution of the NMDA receptors to the field EPSP at the highest blast exposure level. Our results emphasize the need to account for the effects of primary blast loading when studying the sequelae of bTBI.

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Section: Discussionmentioning

confidence: 77%

Primary blast injury causes cognitive impairments and hippocampal circuit alterations

Beamer¹,

Tummala²,

Gullotti³

et al. 2016

Experimental Neurology

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“…To exacerbate the direct injury from blast, there is a gradual acute response of systemic hypoxia on the brain in this polytrauma model. Our group has reported that there are minimal effects on the lungs and therefore an absence of systemic hypoxia after blast-induced mTBI [35, 72]. Future studies will examine oxidative stress and susceptibility of blast-induced BBB breakdown in hypoxic environments.…”

Section: Discussionmentioning

confidence: 99%

Distinguishing the Unique Neuropathological Profile of Blast Polytrauma

Hubbard

Greenberg

Norris

et al. 2017

Oxidative Medicine and Cellular Longevity

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Traumatic brain injury sustained after blast exposure (blast-induced TBI) has recently been documented as a growing issue for military personnel. Incidence of injury to organs such as the lungs has decreased, though current epidemiology still causes a great public health burden. In addition, unprotected civilians sustain primary blast lung injury (PBLI) at alarming rates. Often, mild-to-moderate cases of PBLI are survivable with medical intervention, which creates a growing population of survivors of blast-induced polytrauma (BPT) with symptoms from blast-induced mild TBI (mTBI). Currently, there is a lack of preclinical models simulating BPT, which is crucial to identifying unique injury mechanisms of BPT and its management. To meet this need, our group characterized a rodent model of BPT and compared results to a blast-induced mTBI model. Open field (OF) performance trials were performed on rodents at 7 days after injury. Immunohistochemistry was performed to evaluate cellular outcome at day seven following BPT. Levels of reactive astrocytes (GFAP), apoptosis (cleaved caspase-3 expression), and vascular damage (SMI-71) were significantly elevated in BPT compared to blast-induced mTBI. Downstream markers of hypoxia (HIF-1α and VEGF) were higher only after BPT. This study highlights the need for unique therapeutics and prehospital management when handling BPT.

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“…Specifically, learning and memory has been shown to be associated with abnormal levels of myo-inositol, which is an astrogliosis marker (Sajja et al, 2014b ). Resultants of gliosis directed toward dementia, such as tau and DNA methylation markers are found to be upregulated following TBI (Bailey et al, 2015 ; Sajja et al, 2015 ; Shultz et al, 2015 ). Another indicator linked to memory deficits is the disrupted homeostasis of extra and intra-cellular K+ channels in glia (D'Ambrosio et al, 1999 ).…”

Section: Glial Contribution To Memory Deficitsmentioning

confidence: 99%

Role of Glia in Memory Deficits Following Traumatic Brain Injury: Biomarkers of Glia Dysfunction

Sajja

Hlavac

VandeVord

2016

Front. Integr. Neurosci.

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Historically, glial cells have been recognized as a structural component of the brain. However, it has become clear that glial cells are intimately involved in the complexities of neural networks and memory formations. Astrocytes, microglia, and oligodendrocytes have dynamic responsibilities which substantially impact neuronal function and activities. Moreover, the importance of glia following brain injury has come to the forefront in discussions to improve axonal regeneration and functional recovery. The numerous activities of glia following injury can either promote recovery or underlie the pathobiology of memory deficits. This review outlines the pathological states of glial cells which evolve from their positive supporting roles to those which disrupt synaptic function and neuroplasticity following injury. Evidence suggests that glial cells interact extensively with neurons both chemically and physically, reinforcing their role as pivotal for higher brain functions such as learning and memory. Collectively, this mini review surveys investigations of how glial dysfunction following brain injury can alter mechanisms of synaptic plasticity and how this may be related to an increased risk for persistent memory deficits. We also include recent findings, that demonstrate new molecular avenues for clinical biomarker discovery.

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Enduring deficits in memory and neuronal pathology after blast-induced traumatic brain injury

Cited by 52 publications

References 47 publications

Primary blast injury causes cognitive impairments and hippocampal circuit alterations

Primary blast injury causes cognitive impairments and hippocampal circuit alterations

Distinguishing the Unique Neuropathological Profile of Blast Polytrauma

Role of Glia in Memory Deficits Following Traumatic Brain Injury: Biomarkers of Glia Dysfunction

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