Toll like receptor 4 activation can be either detrimental or beneficial following mild repetitive traumatic brain injury depending on timing of activation

Corrigan, Frances; Arulsamy, Alina; Collins-Praino, Lyndsey E.; Holmes, Joshua L; Vink, Robert

doi:10.1016/j.bbi.2017.04.006

Cited by 38 publications

(20 citation statements)

References 93 publications

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“…These results are in agreement with previous findings of increased overall locomotor activity following injury in the open field test (Budinich et al, 2013, B. et al, 2017, Corrigan et al, 2017). Notably, however, the lack of an effect on locomotion in the EZM and EPM, along with enhancement, rather than impairment, in locomotion in the OF, suggests that it is not a confounding factor for the observed differences in anxiety-like behavior between the vulnerable and resilient groups.…”

Section: Resultssupporting

confidence: 94%

Neural markers of vulnerability to anxiety outcomes following traumatic brain injury

Popovitz

Mysore

Adwanikar³

2020

Preprint

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11Anxiety outcomes following traumatic brain injury (TBI) are complex, and the underlying neural 12 mechanisms are poorly understood. Here, we developed a multidimensional behavioral profiling 13 approach to investigate anxiety-like outcomes in mice that takes into account individual variability. 14 Departing from the tradition of comparing outcomes in TBI versus sham groups, we identified animals 15 within the TBI group that are vulnerable to anxiety dysfunction by applying dimensionality reduction, 16 clustering and post-hoc validation to behavioral data obtained from multiple assays for anxiety at 17 several post-injury timepoints. These vulnerable animals expressed distinct molecular profiles in the 18 corticolimbic network, with downregulation in GABA and glutamate, and upregulation in NPY 19 markers. Indeed, among vulnerable animals, not resilient or sham controls, severity of anxiety 20 outcomes correlated strongly with expression of molecular markers. Our results establish a 21 foundational approach, with predictive power, for reliably identifying maladaptive anxiety outcomes 22 following TBI and uncovering neural signatures of vulnerability to anxiety.23 24 101 sections (Methods).102 103 Figure 1. Multidimensional behavioral clustering with validation (MBCV) for identifying animals 104 vulnerable to anxiety after TBI 105 (A) Experimental timeline and protocol for measuring anxiety-like behaviors before and after injury. EZM 106 -elevated zero maze; OFT -open field test; EPM -elevated zero maze; all standard assays for 107 5 measuring anxiety-like behaviors in rodents. CCI -Controlled cortical impact injury model. IHC -108 immunohistochemistry. 109 (B) Anxiety behavioral 'profile' of a mouse: A 11-dimensional vector which combines behavioral data on 110 the EZM, OFT and EPM across time points. Each element in the vector is the proportion of time spent by 111 the mouse in the anxiogenic zones of one of the assays (ex. EZM) at one of the post-injury time points 112 (ex. Week 7), normalized to the animal's pre-injury baseline value in that assay (Methods). 113(C) Multidimensional behavioral clustering with validation approach: Behavioral profiles of mice exposed 114 TBI are first subject to principal components analysis (PCA), and then to k-means clustering (with k=2) to 115 identify two clusters in principal component (PC) space. The final validation step determines (i) whether 116 animals in the two clusters exhibit distinct anxiety phenotypes after TBI, and if so, (ii) whether (and 117 which) cluster consists of animals vulnerable to anxiety outcomes after TBI. This involves plotting and 118 comparing between the clusters, anxiety metrics from each assay. 120We asked if, based on their multidimensional anxiety behavioral profiles, mice that underwent TBI could 121 be separated into two distinct groups such that one exhibited severe affective behavioral consequences 122 of injury, and the other was largely resistant to effects of injury. To address this question, we developed 123 a data-driven approach. W...

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Section: Resultssupporting

confidence: 94%

Neural markers of vulnerability to anxiety outcomes following traumatic brain injury

Popovitz

Mysore

Adwanikar³

2020

Preprint

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“…These include both severe and mild injury severities, and incorporate a variety of TBI models, including weight drop, the CCI model, fluid percussion injury, and blast injury. 96,[157][158][159][160][161][162][163][164][165][166] Though, as shown in Table 1, the forced swim and tail suspension tests do not always provide positive data, the depressive phenotype observed in some models of TBI allows investigation of new therapeutics. Indeed, several diverse pharmacological approaches have demonstrated improvements in TBI-associated depression-like behaviors, including inhibition of glycogen synthase kinase 3, 157 anti-inflammatory agents, 161 as well as CB2 cannabinoid receptor inverse agonism.…”

Section: Cognitive Tasks and Impairments In Rodent Traumatic Brain Inmentioning

confidence: 99%

Clinical Relevance of Behavior Testing in Animal Models of Traumatic Brain Injury

Shultz

McDonald

Corrigan

et al. 2020

Journal of Neurotrauma

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Traumatic brain injury (TBI) is a leading cause of morbidity worldwide, with patients often suffering from consequences such as cognitive deficits, social abnormalities, anxiety, depression, pain, and motor dysfunction. Given that these impairments often have a significant impact on the patient's quality of life, a key aim of therapeutic intervention in TBI is to mitigate these effects. Translational strategies to develop such interventions have heavily featured animal models of TBI. To assess the efficacy of interventions in these models, a range of behavioral outcomes are utilized. However, in light of the past translational failures that have plagued the TBI field, the clinical relevance of these preclinical behavioral tests is now being scrutinized. This article will summarize the behavioral consequences of TBI in humans; describe common methods available for testing cognition, social function, motor ability, pain, as well as depression-and anxiety-like behaviors in animal models of TBI; provide an overview of the results from TBI animal model studies that have utilized these methods; and discuss these pre-clinical behavior methods and findings in terms of their relevance to the clinical TBI setting. We conclude that there is translational value in these methods and their related findings, but also suggest strategies and future research to improve the clinical relevance of behavior testing in animal models of TBI.

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“…One group considered this question and determined that timing of LPS treatment mediated a beneficial or detrimental post-injury effect in rats. For example, LPS treatment 1 day after repetitive mild TBI (3 TBI’s, 5 days apart) increased macrophage reactivity but decreased production of inflammatory cytokines and reduced neuronal injury ( 235 ). Delayed LPS treatment 5 days after repetitive TBI increased inflammatory cytokines, worsened neuronal damage including phosphorylation and aggregation of tau, and impaired behavioral recovery ( 235 ).…”

Section: Post-injury Peripheral Immune Challenge Worsens Recovery Folmentioning

confidence: 99%

“…For example, LPS treatment 1 day after repetitive mild TBI (3 TBI’s, 5 days apart) increased macrophage reactivity but decreased production of inflammatory cytokines and reduced neuronal injury ( 235 ). Delayed LPS treatment 5 days after repetitive TBI increased inflammatory cytokines, worsened neuronal damage including phosphorylation and aggregation of tau, and impaired behavioral recovery ( 235 ). These results highlight the temporal immune response to TBI and indicate that delayed post-injury immune challenges are detrimental to outcome.…”

Section: Post-injury Peripheral Immune Challenge Worsens Recovery Folmentioning

confidence: 99%

The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease

2018

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The post-injury inflammatory response is a key mediator in long-term recovery from traumatic brain injury (TBI). Moreover, the immune response to TBI, mediated by microglia and macrophages, is influenced by existing brain pathology and by secondary immune challenges. For example, recent evidence shows that the presence of beta-amyloid and phosphorylated tau protein, two hallmark features of AD that increase during normal aging, substantially alter the macrophage response to TBI. Additional data demonstrate that post-injury microglia are “primed” and become hyper-reactive following a subsequent acute immune challenge thereby worsening recovery. These alterations may increase the incidence of neuropsychiatric complications after TBI and may also increase the frequency of neurodegenerative pathology. Therefore, the purpose of this review is to summarize experimental studies examining the relationship between TBI and development of AD-like pathology with an emphasis on the acute and chronic microglial and macrophage response following injury. Furthermore, studies will be highlighted that examine the degree to which beta-amyloid and tau accumulation as well as pre- and post-injury immune stressors influence outcome after TBI. Collectively, the studies described in this review suggest that the brain’s immune response to injury is a key mediator in recovery, and if compromised by previous, coincident, or subsequent immune stressors, post-injury pathology and behavioral recovery will be altered.

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Toll like receptor 4 activation can be either detrimental or beneficial following mild repetitive traumatic brain injury depending on timing of activation

Cited by 38 publications

References 93 publications

Neural markers of vulnerability to anxiety outcomes following traumatic brain injury

Neural markers of vulnerability to anxiety outcomes following traumatic brain injury

Clinical Relevance of Behavior Testing in Animal Models of Traumatic Brain Injury

The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease

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