Ocular blast trauma induces multiple pathological changes in the retina and optic nerve that can result in permanent vision loss. Previous research has focused on characterizing various models of whole body or head blast injury in rodents. We characterized the response of ocular blast injury in three genetically distinct inbred strains of mice (C57Bl/6J, DBA/2J and Balb/cJ) to determine if genetic susceptibility played a role in the pathogenesis. The DBA/2J and Balb/cJ mouse strains were the most susceptible to ocular blast injury, so we used these strains to test the efficacy of erythropoietin (EPO), a neuroprotective cytokine, as a therapeutic agent for ocular blast injury. EPO either protected against or exacerbated the injury, which was dependent upon treatment timing. We found that early treatment with EPO elevated retinal iron levels and likely caused increased oxidative stress through the Fenton reaction. Additionally, we assessed the role of oxidative stress in ocular blast injury using the Gulo-/- mouse, which lacks the enzyme necessary for vitamin C synthesis and exhibits increased oxidative stress in neuronal tissue. The Gulo-/- mouse exhibited a similar injury phenotype to the control strain, the C57B/6J. This may be due to vitamin Câs inability to effectively prevent peroxynitrite formation, a potential key mediator of the pathogenesis of ocular blast injury.

The perceptual binding of sensory signals from different sensory modalities is essential for the development of a coherent perception of the world. The behavioral benefits of multisensory interactions are readily evident as the interaction of auditory and visual cues enhances the comprehension of speech. An essential property for determining if these sensory signals will be perceptually bound is the temporal relationship between sensory signals. The perceptual binding of sensory signals occurs over a range of time when the signals may be proximate but asynchronous. This epoch of time during which multisensory interactions are likely to occur has been termed the temporal binding window (TBW). Recently, several studies have reported that the TBW for typically developed adults is capable of being altered by perceptual training. The following studies were conducted to determine the manner and contingencies with which multisensory perceptual learning occurs, the capacity for multisensory perceptual learning to enhance temporal acuity for audiovisual speech, and the neural correlates of perceptual learning to enhance temporal acuity for audiovisual speech. These studies have collectively enhanced our understanding of perceptual learning.

Alzheimerâs disease (AD) is the most common form of dementia. There is currently no treatment that will delay, halt, or prevent the onset of AD. If a disease modifying therapy were to be implemented, it has been proposed that the earliest stages of the disease must be identified to target individuals in whom treatment would be most effective. The aim of this study was to examine subtle changes in cognition and physiology in middle aged (40-60 years old) subjects at increased risk for AD due to family history. To accomplish this, the project used cognitive tasks that were developed to target specific subregions of the medial temporal lobe, the first area of the brain impacted by AD pathology. Additionally, neuroimaging was used to characterize cerebrovascular function using two metrics: cerebral blood flow (CBF) and cerebrovascular reactivity (CVR). Finally, the relationship between cognitive testing and cerebrovascular function was analyzed. Results showed that the at risk group performed worse on a number of cognitive tests targeting subregions first affected by AD pathology. In contrast, there were no differences between groups in cerebrovascular function or brain volumes. However, CVR correlated with several cognitive tests in the at risk group. These results indicate that there are subtle cognitive differences between middle aged subjects at risk for AD and control subjects, and these differences are likely driven by AD pathology. While there were no group differences in neurovascular function, it is possible that cerebrovascular reactivity may influence individual cognitive performance in these at risk subjects.

Huntingtonâs disease (HD) is caused by an increase in CAG repeats in exon 1 of the huntingtin gene (HTT), which results in a polyglutamine expansion in the HTT protein. This mutation causes profound striatal neurodegeneration through an unknown mechanism, which adversely affects multiple cellular processes including DNA repair, autophagy, vesicular transport and neuronal metal homeostasis. Many neuronal enzymes require metals as cofactors, including several within the partial urea cycle which functions in brain. Perturbations in the urea cycle have been reported in HD models and in HD patient blood and brain. In neurons, arginase is a central urea cycle enzyme, and the metal manganese (Mn) is an essential cofactor. Deficient biological responses to Mn, and reduced Mn accumulation have been observed in HD striatal mouse and cell models. Here we report in vivo and ex vivo evidence of a urea cycle metabolic phenotype in a prodromal HD mouse model. Further, either in vivo or in vitro Mn supplementation reverses the urea-cycle pathology by restoring arginase activity. We show that Arginase 2 (ARG2) not Arginase 1 (ARG1) is the arginase enzyme present in these mouse brain models, with ARG2 protein levels directly increased by Mn exposure without change in gene expression levels. ARG2 protein is not reduced in the prodromal stage, though enzyme activity is reduced, indicating that it is the altered Mn bioavailability as a cofactor that leads to the deficient enzymatic activity. These data support a hypothesis that mutant HTT leads to a selective deficiency of neuronal Mn at an early disease stage. This Mn deficiency contributes to HD striatal urea-cycle pathophysiology through an effect on ARG2.

Punishment undergirds large-scale cooperation and helps dispense criminal justice. Despite its importance, little is known about the brain mechanisms that support punishment decision-making as well as the influence of affect on these brain systems. Across four studies I explore these twin questions. Prior behavioral studies indicate that the mental state of the offender and the harm he caused are the primary factors that influence the outcome of a punishment decision. Chapter one examines how people assess the mental states of offenders, evaluate the harms they caused, and integrate those two components into a single punishment decision. Using a new design, we isolated these three processes, identifying the distinct brain systems and activities that enable each. Additional findings suggest that the amygdala plays a crucial role in mediating the interaction of mental state and harm information, whereas the dorsolateral prefrontal cortex plays a crucial, final-stage role, both in integrating mental state and harm information and in selecting a suitable punishment amount. Chapter two builds on chapter one to explore the role of affective arousal in shifting the outcome of the punishment decision. Specifically, we use a subliminal cue that is known to target activation in the amygdala and assess the extent to which there may be a causal link between the amygdala and punishment decisions. In chapters three and four I expand on the role of emotional affect in third-party punishment decision-making by parsing the specific emotional state that is associated with mediating the relationship between norm violations and punishment outcomes. Inconsistent with the popular notion that punishment decisions are based on purely cognitive reasoning, intended harmful acts elicit strong emotional reactions in third-party decision makers. While these emotional responses are now believed to affect punishment decision-making, there is much debate about what emotions may be fueling this behavior. Chapter three demonstrates thatâunlike anger, contempt, and disgustâmoral outrage is evoked by the integration of culpable mental state and resulting harms, and it alone mediates the relationship between this integrative process and punishment decisions. Chapter four demonstrates that moral outrage appears to be selective for third-party norm violations.

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