Brain-wide reconstruction of inhibitory circuits after traumatic brain injury.
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ABSTRACT:
SUBMITTER: Frankowski JC
PROVIDER: S-EPMC9197933 | biostudies-literature | 2022 Jun
REPOSITORIES: biostudies-literature
Publications
Brain-wide reconstruction of inhibitory circuits after traumatic brain injury.
Frankowski Jan C JC Tierno Alexa A Pavani Shreya S Cao Quincy Q Lyon David C DC Hunt Robert F RF
Nature communications 20220614 1
Despite the fundamental importance of understanding the brain's wiring diagram, our knowledge of how neuronal connectivity is rewired by traumatic brain injury remains remarkably incomplete. Here we use cellular resolution whole-brain imaging to generate brain-wide maps of the input to inhibitory neurons in a mouse model of traumatic brain injury. We find that somatostatin interneurons are converted into hyperconnected hubs in multiple brain regions, with rich local network connections but dimin ...[more]
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Project description:Being able to focus on a complex task and inhibit unwanted actions or interfering information (i.e., inhibitory control) are essential human cognitive abilities. However, it remains unknown the extent to which mild traumatic brain injury (mTBI) may impact these critical functions. In this study, seventeen patients and age-matched healthy controls (HC) performed a variant of the Stroop task and attention-demanding 4-choice response tasks (4CRT) with identical stimuli but two contexts: one required only routine responses and the other with occasional response conflicts. The results showed that mTBI patients performed equally well as the HC when the 4CRT required only routine responses. However, when the task conditions included occasional response conflicts, mTBI patients with even a single concussion showed a significant slow-down in all responses and higher error rates relative to the HC. Results from event-related functional magnetic resonance imaging (efMRI) revealed altered neural activity in the mTBI patients in the cerebellum-thalamo-cortical and the fronto-basal-ganglia networks regulating inhibitory control. These results suggest that even without apparent difficulties in performing complex attention-demanding but routine tasks, patients with mTBI may experience long-lasting deficits in regulating inhibitory control when situations call for rapid conflict resolutions.
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Project description:BackgroundFactors such as age, pre-injury health, and injury severity, account for less than 35% of outcome variability in traumatic brain injury (TBI). While some residual outcome variability may be attributable to genetic factors, published candidate gene association studies have often been underpowered and subject to publication bias.MethodsWe performed the first genome- and transcriptome-wide association studies (GWAS, TWAS) of genetic effects on outcome in TBI. The study population consisted of 5268 patients from prospective European and US studies, who attended hospital within 24 h of TBI, and satisfied local protocols for computed tomography.FindingsThe estimated heritability of TBI outcome was 0·26. GWAS revealed no genetic variants with genome-wide significance (p < 5 × 10-8), but identified 83 variants in 13 independent loci which met a lower pre-specified sub-genomic statistical threshold (p < 10-5). Similarly, none of the genes tested in TWAS met tissue-wide significance. An exploratory analysis of 75 published candidate variants associated with 28 genes revealed one replicable variant (rs1800450 in the MBL2 gene) which retained significance after correction for multiple comparison (p = 5·24 × 10-4).InterpretationWhile multiple novel loci reached less stringent thresholds, none achieved genome-wide significance. The overall heritability estimate, however, is consistent with the hypothesis that common genetic variation substantially contributes to inter-individual variability in TBI outcome. The meta-analytic approach to the GWAS and the availability of summary data allows for a continuous extension with additional cohorts as data becomes available.FundingA full list of funding bodies that contributed to this study can be found in the Acknowledgements section.
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Project description:Traumatic brain injury represents a significant global health burden and has the highest prevalence among neurological disorders. Even mild traumatic brain injury can induce subtle, long-lasting changes that increase the risk of future neurodegeneration. Importantly, this can be challenging to detect through conventional neurological assessment. This underscores the need for more sensitive diagnostic tools, such as electroencephalography, to uncover opportunities for therapeutic intervention. Progress in the field has been hindered by a lack of studies linking mechanistic insights at the microscopic level from animal models to the macroscale phenotypes observed in clinical imaging. Our study addresses this gap by investigating a rat model of mild blast traumatic brain injury using both immunohistochemical staining of inhibitory interneurons and translationally relevant electroencephalography recordings. Although we observed no pronounced effects immediately post-injury, chronic time points revealed broadband hyperexcitability and increased connectivity, accompanied by decreased density of inhibitory interneurons. This pattern suggests a disruption in the balance between excitation and inhibition, providing a crucial link between cellular mechanisms and clinical hallmarks of injury. Our findings have significant implications for the diagnosis, monitoring, and treatment of traumatic brain injury. The emergence of electroencephalography abnormalities at chronic time points, despite the absence of immediate effects, highlights the importance of long-term monitoring in traumatic brain injury patients. The observed decrease in inhibitory interneuron density offers a potential cellular mechanism underlying the electroencephalography changes and may represent a target for therapeutic intervention. This study demonstrates the value of combining cellular-level analysis with macroscale neurophysiological recordings in animal models to elucidate the pathophysiology of traumatic brain injury. Future research should focus on translating these findings to human studies and exploring potential therapeutic strategies targeting the excitation-inhibition imbalance in traumatic brain injury.
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Project description:Time dependent-profiles in the gene expression level following lateral moderate fluid percussion injury in the rat brain We used microarray to elucidate relationship between the alteration of gene expression levels and the progression of brain damages following traumatic brain injury. To examine the levels of gene expression in the early phase of traumatic brain injury, we analyzed the gene expression at 3, 6, 12, and 48 h after trauma using the lateral moderate fluid percussion TBI model. The ratios of the gene expression level were compared between chips corresponding to the 3, 6 and 12 h fluid percussion groups and the sham group chips. On the other hand, the rations of gene expression level after 48 h FPI were compared with 48 h sham chip, because the gene expression levels of 48 h sham chip were distinct from sham group chips (3, 6 and 12 h) in the cluster and principal components analyses.
2010-12-07 | E-GEOD-24047 | biostudies-arrayexpress
Project description:OBJECTIVES:To determine the mechanism of action of valproic acid (VPA) in the adult central nervous system (CNS) following traumatic brain injury (TBI) and hemorrhagic shock (HS). METHODS:Data were analyzed from different sources, including experiments in a porcine model, data from postmortem human brain, published studies, public and commercial databases. RESULTS:The transcriptional program in the CNS following TBI, HS, and VPA treatment includes activation of regulatory pathways that enhance neurogenesis and suppress gliogenesis. Genes which encode the transcription factors (TFs) that specify neuronal cell fate, including MEF2D, MYT1L, NEUROD1, PAX6 and TBR1, and their target genes, are induced by VPA. VPA represses genes responsible for oligodendrogenesis, maintenance of white matter, T-cell activation, angiogenesis, and endothelial cell proliferation, adhesion and chemotaxis. NEUROD1 has regulatory interactions with 38% of the genes regulated by VPA in a swine model of TBI and HS in adult brain. Hi-C spatial mapping of a VPA pharmacogenomic SNP in the GRIN2B gene shows it is part of a transcriptional hub that contacts 12 genes that mediate chromatin-mediated neurogenesis and neuroplasticity. CONCLUSIONS:Following TBI and HS, this study shows that VPA administration acts in the adult brain through differential activation of TFs responsible for neurogenesis, genes responsible for neuroplasticity, and repression of TFs that specify oligodendrocyte cell fate, endothelial cell chemotaxis and angiogenesis. Short title: Mechanism of action of valproic acid in traumatic brain injury.
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Project description:Traumatic brain injury (TBI) is associated with greater 'brain age' that may be caused by atrophy in grey and white matter. Here, we investigated 'brain age' in a chronic TBI (≥10 years) sample. We examined whether 'brain age' increases with years post injury, and whether it is associated with injury severity, cognition and functional outcome. We recruited 102 participants with moderate to severe TBI aged between 40 and 85 years. TBI participants were assessed on average 22 years post-injury. Seventy-seven healthy controls were also recruited. Participants' 'brain age' was determined using T1-weighted MRI images. TBI participants were estimated to have greater 'brain age' compared to healthy controls. 'Brain age' gap was unrelated to time since injury or long-term functional outcome on the Glasgow Outcome Scale-Extended. Greater brain age was associated with greater injury severity measured by post traumatic amnesia duration and Glasgow Coma Scale. 'Brain age' was significantly and inversely associated with verbal memory, but unrelated to visual memory/ability and cognitive flexibility and processing speed. A longitudinal study is required to determine whether TBI leads to a 'one-off' change in 'brain age' or progressive ageing of the brain over time.
| S-EPMC9117693 | biostudies-literature
Project description:Traumatic brain injury (TBI) represents the leading cause of death in young individuals. It triggers the accumulation of harmful mediators, leading to secondary damage, yet protective mechanisms are also set in motion. The endocannabinoid (eCB) system consists of ligands, such as anandamide and 2-arachidonoyl-glycerol (2-AG), receptors (e.g. CB1, CB2), transporters and enzymes, which are responsible for the 'on-demand' synthesis and degradation of these lipid mediators. There is a large body of evidence showing that eCB are markedly increased in response to pathogenic events. This fact, as well as numerous studies on experimental models of brain toxicity, neuroinflammation and trauma supports the notion that the eCB are part of the brain's compensatory or repair mechanisms. These are mediated via CB receptors signalling pathways that are linked to neuronal survival and repair. The levels of 2-AG, the most highly abundant eCB, are significantly elevated after TBI and when administered to TBI mice, 2-AG decreases brain oedema, inflammation and infarct volume and improves clinical recovery. The role of CB1 in mediating these effects was demonstrated using selective antagonists or CB1 knockout mice. CB2 were shown in other models of brain insults to reduce white blood cell rolling and adhesion, to reduce infarct size and to improve motor function. This review is focused on the role the eCB system plays as a self-neuroprotective mechanism and its potential as a basis for the development of novel therapeutic modality for the treatment of CNS pathologies with special emphasis on TBI.
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Project description:BackgroundHypothermia has been used in the treatment of brain injury for many years. Encouraging results from small trials and laboratory studies led to renewed interest in the area and some larger trials.ObjectivesTo determine the effect of mild hypothermia for traumatic brain injury (TBI) on mortality, long-term functional outcomes and complications.Search methodsWe ran and incorporated studies from database searches to 21 March 2016. We searched the Cochrane Injuries Group's Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE (OvidSP), Embase Classic+Embase (OvidSP), PubMed, ISI Web of science (SCI-EXPANDED, SSCI, CPCI-S & CPSI-SSH), clinical trials registers, and screened reference lists. We also re-ran these searches pre-publication in June 2017; the result from this search is presented in 'Studies awaiting classification'.Selection criteriaWe included randomised controlled trials of participants with closed TBI requiring hospitalisation who were treated with hypothermia to a maximum of 35 ºC for at least 12 consecutive hours. Treatment with hypothermia was compared to maintenance with normothermia (36.5 to 38 ºC).Data collection and analysisTwo review authors assessed data on mortality, unfavourable outcomes according to the Glasgow Outcome Scale, and pneumonia.Main resultsWe included 37 eligible trials with a total of 3110 randomised participants; nine of these were new studies since the last update (2009) and five studies had been previously excluded but were re-assessed and included during the 2017 update. We identified two ongoing studies from searches of clinical trials registers and database searches and two studies await classification.Studies included both adults and children with TBI. Most studies commenced treatment immediately on admission to hospital or after craniotomies and all treatment was maintained for at least 24 hours. Thirty-three studies reported data for mortality, 31 studies reported data for unfavourable outcomes (death, vegetative state or severe disability), and 14 studies reported pneumonia. Visual inspection of the results for these outcomes showed inconsistencies among studies, with differences in the direction of effect, and we did not pool these data for meta-analysis. We considered duration of hypothermia therapy and the length of follow-up in collected data for these subgroups; differences in study data remained such that we did not perform meta-analysis.Studies were generally poorly reported and we were unable to assess risk of bias adequately. Heterogeneity was evident both in the trial designs and participant inclusion. Inconsistencies in results may be explained by heterogeneity among study participants or bias introduced by individual study methodology but we did not explore this in detail in subgroup or sensitivity analyses. We used the GRADE approach to judge the quality of the evidence for each outcome and downgraded the evidence for mortality and unfavourable outcome to very low. We downgraded the evidence for the pneumonia outcome to low.Authors' conclusionsDespite a large number studies, there remains no high-quality evidence that hypothermia is beneficial in the treatment of people with TBI. Further research, which is methodologically robust, is required in this field to establish the effect of hypothermia for people with TBI.
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Project description:Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide. Despite extensive preclinical research supporting the effectiveness of neuroprotective therapies for brain trauma, there have been no successful randomized controlled clinical trials to date. TBI results in delayed secondary tissue injury due to neurochemical, metabolic and cellular changes; modulating such effects has provided the basis for neuroprotective interventions. To establish more effective neuroprotective treatments for TBI it is essential to better understand the complex cellular and molecular events that contribute to secondary injury. Here we critically review relevant research related to causes and modulation of delayed tissue damage, with particular emphasis on cell death mechanisms and post-traumatic neuroinflammation. We discuss the concept of utilizing multipotential drugs that target multiple secondary injury pathways, rather than more specific "laser"-targeted strategies that have uniformly failed in clinical trials. Moreover, we assess data supporting use of neuroprotective drugs that are currently being evaluated in human clinical trials for TBI, as well as promising emerging experimental multipotential drug treatment strategies. Finally, we describe key challenges and provide suggestions to improve the likelihood of successful clinical translation.
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Project description:Leukemia inhibitory factor (LIF) is a neuroprotective cytokine that is essential for appropriate glial responses, remyelination, and preservation of neuronal conductance after injury. The intranasal route for delivery of therapeutics to the central nervous system is of particular interest given that it bypasses the blood-brain barrier and peripheral clearance systems. We explored the possibility that LIF might improve neurological function when administered intranasally during the acute phase in a pediatric model of mild traumatic brain injury (mTBI). We tested two doses of LIF and evaluated behavioral outcomes. Here, we show that acute 40-ng intranasal LIF treatment twice a day for 3 days attenuates astrogliosis and microgliosis, protects against axonal damage, significantly improves sensorimotor function, and is well tolerated without detrimental effects on growth. Altogether, our studies provide pre-clinical evidence for the use of acute intranasal LIF treatment as a viable therapeutic for pediatric cases of mTBIs.
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