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Temporal Evolution of Heme Oxygenase-1 Expression in Reactive Astrocytes and Microglia Following Traumatic Brain Injury
Get PDFHeme oxygenase-1 (HO-1) is an inducible enzyme that catabolizes heme into biliverdin (which is converted to bilirubin), carbon monoxide, and free iron. Free iron, particularly Fe2+, is known to have cytotoxic effects, largely via the Fenton reaction. Alternatively, bilirubin and carbon monoxide have been shown to have antioxidant and anti-inflammatory functions, respectively, making the effects of HO-1 difficult to predict. In intracerebral hemorrhage, enhanced HO-1 expression has been reported to be beneficial. However, it is unknown if HO-1 expression has neuroprotective or neurodegenerative sequelae after traumatic brain injury (TBI). In our male mouse study, we quantitatively investigated HO-1 expression in reactive astrocytes and microglia in a controlled cortical impact (CCI) model of TBI at 1, 7, 14, and 30 days post-injury (dpi). Immunoglobulin G (IgG) staining as a measure of blood-brain barrier (BBB) permeability was significantly higher in 1 and 7dpi mice compared to controls, indicating BBB disruption early after TBI. HO-1 expression in astrocytes was significantly increased acutely and subacutely (1, 7, 14dpi) compared to controls. In contrast, significantly elevated expression of HO-1 in microglia was only observed at the chronic 14 and 30dpi time points relative to controls. This study demonstrates that HO-1 is highly expressed after TBI, but primarily in cells that contribute to the neuroinflammatory response and modulating this expression may provide a path to therapeutic intervention
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Early life adversity in mice enhances structural reward circuit connectivity during development and leads to enduring adaptations into adulthood
Get PDFEarly life adversity (ELA) comprises a wide variety of negative experiences during early life and has been linked to cognitive impairments, reduced experiences of pleasure (anhedonia), and other long-term consequences implying that ELA impacts the reward circuitry. In these studies, we probed the effects of ELA on reward connectivity, structural integrity of the DR-VTA-NAcc projection, and reward behaviors in adulthood. Next we evaluated global and regional brain volume changes after ELA exposure in a sex specific manner, followed by investigation of developmental trajectories of reward regions, their connectivity, and reward behavior. We focused on reward regions, primarily dorsal raphe (DR), ventral tegmental area (VTA), and the nucleus accumbens (NAcc) and the connectivity between these regions. We hypothesized that the reward circuitry would be modified by ELA and emerges early in development and could be observed in adulthood. We used the limited bedding and nesting model to induce ELA in mice and measured reward-related behaviors in development and adulthood using the three-chamber social interaction and sucrose preference tests. High resolution ex vivo diffusion tensor imaging (DTI) was utilized for regional DTI metrics, network measures, and tractography to assess circuit organization. We also used T2-weighted imaging (T2WI) in order to evaluate brain volumes. We found brain-wide changes in brain volume and diffusion metrics in adulthood. We identified increased connectivity of the VTA-NAcc circuit in both development and adulthood. The increased connectivity was associated with augmented maturation and complexity of the reward circuits of ELA males at PND 30. Increased radial diffusivity within the NAcc and increased axial diffusivity within the VTA segment of the DR-VTA-NAcc projections are consistent with modified projections in adulthood. Behaviorally, ELA elicited an increase in sociability at PND 30 that was decreased in adults. Our findings suggest ELA enhances structural reward circuit connectivity during development and leads to enduring circuit adaptations into adulthood. These studies aid the characterization of critical reward circuits and their development following ELA, providing additional understanding of the mechanisms that contribute to negative outcomes later in life
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Neuropathology Following Repeated Traumatic Brain Injury and the Influence of Inflammatory Status on Injury Outcome
Get PDFABSTRACT OF THE DISSERTATIONNeuropathology Following Repeated Traumatic Brain Injury and the Influence of Inflammatory Status on Injury OutcomebyVirginia Dorothy-Marie DonovanDoctor of Philosophy, Graduate Program in Cell, Molecular, and Developmental Biology ProgramUniversity of California, Riverside, August 2014Dr. Andy Obenaus, Co-ChairpersonDr. Monica J. Carson, Co-ChairpersonTraumatic brain injury (TBI) is an increasing public health concern, accounting for approximately 30% of injury related deaths. Clinical and experimental studies have demonstrated that the brain remains vulnerable following TBI and subsequent injuries may worsen tissue damage. Following injury, microglia, the brain macrophage, have demonstrated both cytotoxic and cytoprotective functions. However, the role of microglial activation in injury progression and resolution is not understood. This dissertation examines the progression of tissue damage following repeated mild TBI (rmTBI) and investigates whether inflammatory status at the time of a moderate-to-severe injury influences outcome. Using a novel rmTBI model, we found acute 2-fold increases in tissue damage on T2-weighted magnetic resonance imaging (MRI) when injuries were induced 7 (7D), but not 3 days (3D) apart. Furthermore, injuries 7D apart resulted in 2-fold more blood deposition, while those 3D apart showed more edema. Though sub-acute grey matter pathology was transient. We therefore assessed white matter, not directly underneath the impact, using diffusion tensor MRI and electron microscopy at sub-acute (14-day) and long-term (60-day) timepoints. At sub-acute times, we found that rmTBI 7D apart resulted in white matter changes localized to regions immediately adjacent to the impact sites. However, long-term assessment revealed that changes in white matter integrity within rmTBI animals became widespread. The effect of inflammatory status on TBI induced hemispheric swelling and lesion pathology was tested 7D post injury. We compared MRI pathology with inflammatory molecule expression from naïve, wildtype (TBI; no pre-treatment), wildtype with LPS-challenge 24-hrs before TBI and TREM2KO animals. MRI showed an 80% reduction in hemispheric swelling within TREM2KO and LPS-challenged animals compared to wildtype. Reduced swelling coincided with a 2-fold increase in microglial expression of inflammatory genes compared to naïve animals. However, LPS-challenged and TREM2KO mice showed a reduced inflammatory response from wildtype. Furthermore, comparison of TREM2KO microglia with cortical tissue revealed an opposing number of expressed genes.Overall, these studies demonstrate that (1) brain vulnerability is dependent on the time interval between and location of injuries, (2) rmTBI results in early white matter disruption that progresses long-term and (3) reduced swelling occurs during limited microglial activation
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Pathophysiology of Juvenile Traumatic Brain Injury: Role of Edema and a Potential Treatment
Get PDFTraumatic brain injury (TBI) is caused by an external force to the head, resulting in damage to the brain. TBI is especially common in children and young adults and is associated with long-term mortality and morbidity. Juveniles seem to be at increased risk of developing cerebral edema after TBI partly due to higher water content and developmental differences in the brain's response to injury. Aquaporin-4 (AQP4) is the most abundant water channel in the brain and plays a critical role in edema formation. Edema formation can be attributed to cellular swelling (cytotoxic edema) or breakdown of the blood-brain barrier (BBB). This dissertation examined the lesion composition (percentage of blood and edema) after graded juvenile TBI (jTBI) and role of AQP4 in the normal and pathologic rodent brain. Using an established rodent model of focal jTBI, we characterized the composition of the lesion using magnetic resonance imaging (MRI). We found that 1 day after jTBI, the lesion was ~60% edema and ~40% blood. At 3 days, the edema volume decreased in all severity groups and the extravascular blood volume in the lesion remained unchanged. To understand water mobility in the brain after jTBI, we first evaluated the effects of knocking down AQP4 using RNA interference in an uninjured juvenile rodent brain. We demonstrated that a 27% decrease in AQP4 protein expression, induced by small interfering RNA against AQP4 (siAQP4), lead to a 50% reduction in water mobility using We then investigated the effect of siAQP4 injection in a juvenile rodent brain after TBI. We identified improved neurologic testing and physiologic measures, including reduced edema formation, neuronal cell death, astrogliosis, and BBB, in rat pups treated with siAQP4. Given these results, knock down of AQP4 may prove to be an effective therapy in the early time course after jTBI
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Repair of the Cerebral Vasculature After Traumatic Brain Injury and the Influence of Beta-Catenin in New Vessel Formation and Injury Outcome
Get PDFTraumatic brain injury (TBI) often results in damage to the cerebral vasculature which leads to hypoperfusion, edema, and hemorrhage. Repairing the injured vasculature after TBI is critical for neuroprotection and improving outcomes. While numerous studies have shown that the cerebral vessels are damaged after TBI, there are scant studies looking at repair of the vessel network following brain injury. Furthermore, there is a paucity of studies that have examined the molecular mechanisms underlying vascular repair after TBI. One possible signaling factor is β-catenin, which promotes blood vessel formation during embryonic development. To address this gap in knowledge, we developed a novel method to stain, visualize, and analyze the cerebral vasculature in the entire rodent brain. This technique, referred to as Vessel Painting (VP), effectively stains pial, penetrating, and parenchymal vessels and cerebral vessels can be imaged by wide-field fluorescent microscopy to acquire whole brain images. We introduce two complimentary methods to analyze vessel morphology and complexity in the whole brain. Our novel VP and analysis protocol was used to study the vascular alterations after TBI. Adult male mice received a moderate controlled cortical impact followed by VP at 1 and 7 days post injury (dpi). We assessed β-catenin inside blood vessels around the injury site and utilized a Wnt reporter mouse line (TCF/LEF:H2B-GFP) to monitor Wnt gene expression. We report that TBI results in vascular loss at 1 dpi followed by an increase in new vessels at 7 dpi. We observed an acute increase in β-catenin expression and increased Wnt reporter activity in cerebral vessels after TBI. To assess the role of β-catenin in vascular repair, we utilized Lithium to increase β-catenin expression and JW74 to reduce β-catenin expression. Lithium treatment after TBI enhanced vascular repair and lead to elongated vessel segments at 7 dpi while JW74 treatment after TBI reduced vascular repair and lead to fragmented vessels. Overall, these findings suggest that β-catenin becomes activated after TBI to initiate vascular repair. Treatment strategies to enhance β-catenin appear to contribute to vascular repair after TBI and represents a potential target for future therapeutics
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Magnetic resonance imaging reveals progressive neurodegeneration in the spastic Han Wistar rat
No full textIncludes bibliographical references (leaves 36-39)Acute and chronic neurodegenerative disorders are characterized by excessive activation of glutamate receptors which mediate neuronal death in specific brain regions. The spastic Han-Wistar (sHW) rat suffers from glutamate excitotoxicity resulting in neurodegeneration within the cerebellum (Purkinje cells) and hippocampus (CA3 pyramidal cells). Mutants homozygous for the autosomal trait begin to exhibit motor tremors and hind limb rigidity as early as 25 days of age with progressive symptoms resulting in mortality at around 60 days of age. Non-invasive magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) can be used to identify neurodegeneration in many animal models of disease, and we hypothesized that these imaging modalities could identify altered tissue structures within selected brain regions in the sHW rat. Mutant and normal siblings were imaged at 4.7T using T2-weighted MRI and MRS at 30, 45, and 60 days postnatal. Neurodegeneration in the hippocampus and cerebellum were quantified and whole brain volumes were calculated. MRS assessment of brain metabolites was limited to the right and left hippocampi. At 60 days, animals were sacrificed, and their brains extracted for conventional histology. Quantification of T2-values was sensitive for detecting neurodegeneration in the cerebellum and whole brain of the mutant rat. T2 values showed a significant increase in these regions between the 45 and 60 day time points. In addition, a temporal reduction in whole brain and cerebellar volumes over the 60-day course was seen compared to the normal littermates. However, T2-values and tissue volumes were not significantly altered at any time point (30, 45, 60 days) VI in the hippocampus. Histology revealed signs of CA3 pyramidal cell loss with an apparent collapse of the suprapyramidal blade of the dentate gyrus in the mutant and an increase in Cresyl violet staining in the stratum oriens near the CA3 region in the normal littermate. MRS demonstrated an increase in metabolite levels, specifically the N-acetyl-aspartate and creatine (NAA/Cr) ratio, at 60 days in the mutant. These data suggest that MRI and MRS may be sensitive enough to be used as a diagnostic tool for assessment of pathology in progressive neurodegenerative disorders
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