scholarly journals PET Imaging of Peripheral Benzodiazepine Receptor Standard Uptake Value Increases After Controlled Cortical Impact, a Rodent Model of Traumatic Brain Injury.

2020 ◽  
Author(s):  
Benjamin m Aertker ◽  
Akshita Kumar ◽  
Henry W Caplan ◽  
Fanni B Cardenas ◽  
Charles S Cox ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Corpus Callosum ◽  
Morphological Analysis ◽  
Ex Vivo ◽  
Benzodiazepine Receptor ◽  
Rodent Model ◽  
Peripheral Benzodiazepine Receptor ◽  
Activated Microglia

Abstract Background: Traumatic brain injury (TBI) disrupts the complex arrangement of neuronal and glial cells. As a result of TBI there is activation of microglia. Activated microglia after injury can be measured in vivo by using positron emission topography (PET) ligand peripheral benzodiazepine receptor (PBR28) and their phenotypes (activated vs resting) can be assessed (ex vivo) using morphology. This study aims to utilize in vivo (PET) and ex vivo (morphology) to assess the changes in microglia after a controlled cortical impact (CCI), a rodent model for TBI.Methods: Male Sprague Dawley rats underwent a sham injury or severe CCI. Microglia activation was assessed 120 hours after the injury by PET/CT imaging using the radioligand [11C] PBR-28. Standardized uptake values (PBR28suv) were calculated over the duration of the scan and mean values were compared. In order to verify in vivo results, ex vivo morphological analysis [ramified (resting) or amoeboid-shaped (activated)] was performed (dentate gyrus, corpus callosum and thalamus) with the antibody IBA-1. To further conclude that PBR is a marker for activated microglia after CCI, we examined co-staining of PBR with microglia and astrocytes.Results: In vivo and ex vivo results were complementary. Injured animals displayed greater PBR28suv when compared to sham animals. Immunohistochemistry demonstrated elevated numbers of activated microglia in the ipsilateral dentate gyrus, corpus callosum and thalami of injured animals compared to sham animals. Additionally, PBR co-stained with microglia and not astrocytes.Conclusion: CCI, a rodent model of TBI resulted in a significant increase in PBR28suv due to injury. Similarly, morphological analysis demonstrated a significant increase in amoeboid-shaped (activated) microglia. These results serve as a surrogate marker for increased neuroinflammation in the brains of severely injured animals. PBR28suv can serve as an in vivo tracking system for monitoring neuroinflammation following TBI and cellular therapies.

scholarly journals PET Imaging of Peripheral Benzodiazepine Receptor Standard Uptake Value Increases After Controlled Cortical Impact, a Rodent Model of Traumatic Brain Injury

ASN NEURO ◽  
2021 ◽  
Vol 13 ◽  
pp. 175909142110141
Author(s):  
Benjamin M. Aertker ◽  
Akshita Kumar ◽  
Fanni Cardenas ◽  
Franciska Gudenkauf ◽  
David Sequeira ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Immune Cells ◽  
Ex Vivo ◽  
Benzodiazepine Receptor ◽  
Rodent Model ◽  
Peripheral Benzodiazepine Receptor ◽  
Controlled Cortical Impact ◽  
Amoeboid Microglia

Traumatic brain injury (TBI) is a chronic, life threatening injury for which few effective interventions are available. Evidence in animal models suggests un-checked immune activation may contribute to the pathophysiology. Changes in regional density of active brain microglia can be quantified in vivo with positron emission topography (PET) with the relatively selective radiotracer, peripheral benzodiazepine receptor 28 (11 C-PBR28). Phenotypic assessment (activated vs resting) can subsequently be assessed (ex vivo) using morphological techniques. To elucidate the mechanistic contribution of immune cells in due to TBI, we employed a hybrid approach involving both in vivo (11 C-PBR28 PET) and ex vivo (morphology) to elucidate the role of immune cells in a controlled cortical impact (CCI), a rodent model for TBI. Density of activated brain microglia/macrophages was quantified 120 hours after injury using the standardized uptake value (SUV) approach. Ex vivo morphological analysis from specific brain regions using IBA-1 antibodies differentiated ramified (resting) from amoeboid (activated) immune cells. Additional immunostaining of PBRs facilitated co-localization of PBRs with IBA-1 staining to further validate PET data. Injured animals displayed greater PBR28suv when compared to sham animals. Immunohistochemistry demonstrated elevated density of amoeboid microglia/macrophages in the ipsilateral dentate gyrus, corpus callosum, thalami and injury penumbra of injured animals compared to sham animals. PBR co-stained with amoeboid microglia/macrophages in the injury penumbra and not with astrocytes. These data suggest the technologies evaluated may serve as bio-signatures of neuroinflammation following severe brain injury in small animals, potentially enabling in vivo tracking of neuroinflammation following TBI and cellular-based therapies.

scholarly journals WNT3A Promotes Neuronal Regeneration upon Traumatic Brain Injury

2020 ◽  
Vol 21 (4) ◽  
pp. 1463 ◽  
Author(s):  
Chu-Yuan Chang ◽  
Min-Zong Liang ◽  
Ching-Chih Wu ◽  
Pei-Yuan Huang ◽  
Hong-I Chen ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Cortical Neurons ◽  
Ex Vivo ◽  
Neuronal Regeneration ◽  
Functional Behavior ◽  
Functional Behavior Analysis ◽  
Positive Effect

The treatment of traumatic brain injury (TBI) remains a challenge due to limited knowledge about the mechanisms underlying neuronal regeneration. This current study compared the expression of WNT genes during regeneration of injured cortical neurons. Recombinant WNT3A showed positive effect in promoting neuronal regeneration via in vitro, ex vivo, and in vivo TBI models. Intranasal administration of WNT3A protein to TBI mice increased the number of NeuN+ neurons without affecting GFAP+ glial cells, compared to control mice, as well as retained motor function based on functional behavior analysis. Our findings demonstrated that WNT3A, 8A, 9B, and 10A promote regeneration of injured cortical neurons. Among these WNTs, WNT3A showed the most promising regenerative potential in vivo, ex vivo, and in vitro.

scholarly journals Transplanted Adult Neural Stem Cells Express Sonic Hedgehog In Vivo and Suppress White Matter Neuroinflammation after Experimental Traumatic Brain Injury

2017 ◽  
Vol 2017 ◽  
pp. 1-16 ◽  
Author(s):  
Genevieve M. Sullivan ◽  
Regina C. Armstrong
Keyword(s):  
Traumatic Brain Injury ◽  
Stem Cells ◽  
Brain Injury ◽  
White Matter ◽  
Corpus Callosum ◽  
Neural Stem Cells ◽  
Sonic Hedgehog ◽  
Shh Signaling ◽  
Fluorescent Reporter

Neural stem cells (NSCs) delivered intraventricularly may be therapeutic for diffuse white matter pathology after traumatic brain injury (TBI). To test this concept, NSCs isolated from adult mouse subventricular zone (SVZ) were transplanted into the lateral ventricle of adult mice at two weeks post-TBI followed by analysis at four weeks post-TBI. We examined sonic hedgehog (Shh) signaling as a candidate mechanism by which transplanted NSCs may regulate neuroregeneration and/or neuroinflammation responses of endogenous cells. Mouse fluorescent reporter lines were generated to enable in vivo genetic labeling of cells actively transcribingShhorGli1after transplantation and/or TBI.Gli1transcription is an effective readout for canonical Shh signaling. InShhCreERT2;R26tdTomatomice,Shhwas primarily expressed in neurons and was not upregulated in reactive astrocytes or microglia after TBI. Corroborating results inGli1CreERT2;R26tdTomatomice demonstrated that Shh signaling was not upregulated in the corpus callosum, even after TBI or NSC transplantation. Transplanted NSCs expressedShhin vivo but did not increaseGli1labeling of host SVZ cells. Importantly, NSC transplantation significantly reduced reactive astrogliosis and microglial/macrophage activation in the corpus callosum after TBI. Therefore, intraventricular NSC transplantation after TBI significantly attenuated neuroinflammation, but did not activate host Shh signaling viaGli1transcription.

scholarly journals Transplanted Adult Neural Stem Cells Express Sonic Hedgehog In Vivo and Suppress White Matter Neuroinflammation After Experimental Traumatic Brain Injury

2017 ◽  
Author(s):  
Genevieve M. Sullivan ◽  
Regina C. Armstrong
Keyword(s):  
Traumatic Brain Injury ◽  
Stem Cells ◽  
Brain Injury ◽  
White Matter ◽  
Corpus Callosum ◽  
Neural Stem Cells ◽  
Sonic Hedgehog ◽  
Shh Signaling ◽  
Fluorescent Reporter

ABSTRACTNeural stem cells (NSCs) delivered intraventricularly may be therapeutic for diffuse white matter pathology after traumatic brain injury (TBI). To test this concept, NSCs isolated from adult mouse subventricular zone (SVZ) were transplanted into the lateral ventricle of adult mice at two weeks post-TBI followed by analysis at four weeks post-TBI. We examined Sonic hedgehog (Shh) signaling as a candidate mechanism by which transplanted NSCs may regulate neuroregeneration and/or neuroinflammation responses of endogenous cells. Mouse fluorescent reporter lines were generated to enable in vivo genetic labeling of cells actively transcribing Shh or Gli1 after transplantation and/or TBI. Gli1 transcription is an effective readout for canonical Shh signaling. In ShhCreERT2;R26tdTomato mice, Shh was primarily expressed in neurons and was not upregulated in reactive astrocytes or microglia after TBI. Corroborating results in Gli1CreERT2;R26tdTomato host mice demonstrated Shh signaling was not upregulated in the corpus callosum, even after TBI or NSC transplantation. Transplanted NSC expressed Shh in vivo but did not increase Gli1 labeling of host SVZ cells. Importantly, NSC transplantation significantly reduced reactive astrogliosis and microglial/macrophage activation in the corpus callosum after TBI. Therefore, intraventricular NSC transplantation after TBI significantly attenuated neuroinflammation, but did not activate host Shh signaling via Gli1 transcription.

scholarly journals Neuroanatomy and behavior in mice with a haploinsufficiency of AT-rich interactive domain 1B (ARID1B) throughout development

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
J. Ellegood ◽  
S. P. Petkova ◽  
A. Kinman ◽  
L. R. Qiu ◽  
A. Adhikari ◽  
...  
Keyword(s):  
Corpus Callosum ◽  
Ex Vivo ◽  
Chromatin Modification ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Social Deficits ◽  
Altered Expression ◽  
Developmental Growth ◽  
And Behavior

Abstract Background One of the causal mechanisms underlying neurodevelopmental disorders (NDDs) is chromatin modification and the genes that regulate chromatin. AT-rich interactive domain 1B (ARID1B), a chromatin modifier, has been linked to autism spectrum disorder and to affect rare and inherited genetic variation in a broad set of NDDs. Methods A novel preclinical mouse model of Arid1b deficiency was created and validated to characterize and define neuroanatomical, behavioral and transcriptional phenotypes. Neuroanatomy was assessed ex vivo in adult animals and in vivo longitudinally from birth to adulthood. Behavioral testing was also performed throughout development and tested all aspects of motor, learning, sociability, repetitive behaviors, seizure susceptibility, and general milestones delays. Results We validated decreased Arid1b mRNA and protein in Arid1b+/− mice, with signatures of increased axonal and synaptic gene expression, decreased transcriptional regulator and RNA processing expression in adult Arid1b+/− cerebellum. During neonatal development, Arid1b+/− mice exhibited robust impairments in ultrasonic vocalizations (USVs) and metrics of developmental growth. In addition, a striking sex effect was observed neuroanatomically throughout development. Behaviorally, as adults, Arid1b+/− mice showed low motor skills in open field exploration and normal three-chambered approach. Arid1b+/− mice had learning and memory deficits in novel object recognition but not in visual discrimination and reversal touchscreen tasks. Social interactions in the male–female social dyad with USVs revealed social deficits on some but not all parameters. No repetitive behaviors were observed. Brains of adult Arid1b+/− mice had a smaller cerebellum and a larger hippocampus and corpus callosum. The corpus callosum increase seen here contrasts previous reports which highlight losses in corpus callosum volume in mice and humans. Limitations The behavior and neuroimaging analyses were done on separate cohorts of mice, which did not allow a direct correlation between the imaging and behavioral findings, and the transcriptomic analysis was exploratory, with no validation of altered expression beyond Arid1b. Conclusions This study represents a full validation and investigation of a novel model of Arid1b+/− haploinsufficiency throughout development and highlights the importance of examining both sexes throughout development in NDDs.

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