Subconcussive impacts have become a growing concern particularly with respect to contact sports. It is believed that minimal head impacts can cause cerebral perturbations that initiate an immune response creating a window of vulnerability. Evidence suggests that additional head insults sustained during this window of vulnerability elicit an exaggerated inflammatory response and exacerbate cognitive deficits. Therefore, determining the lower limits of systematic perturbation resulting from low-level impacts is of critical importance in expanding our understanding of cerebral vulnerability and recovery. However, the vast majority of experimental investigations of subconcussion fail to model single impact events and instead focus on cumulative insults. Additionally, these animal models employ impact magnitudes used to model mild Traumatic Brain Injury. The present investigation aimed to address this gap in knowledge through the utilization of a pneumatically controlled, closed-head, blunt impact device capable of producing repeatable, defined, subconcussive head impacts within a rat model. Thermography was used as a noninvasive measure of inflammation and system perturbations with respect to local (head) and global (thorax and abdomen) temperature changes. Cognitive function was assessed using an Open Field Test and Novel Object Recognition test. Neuroinflammation was measured by assessment of GFAP and iba-1 within the hippocampus and corpus callosum. To investigate the tolerance and the persistence of cerebral vulnerability, measurement outcomes were assessed at six timepoints of recovery, 0, 0.5, 1, 4, 7, and 14 days. Thermal disturbances were detected directly after impact, followed by an apparent recovery, 0.5- and 1-day post-impact. A latent temperature increase was observed after 4- and 7-days of recovery coinciding with decreased risk-avoidance behaviors, a modest upregulation of iba-1, and a marked downregulation of GFAP. Short-term memory deficits became apparent after 7-days of recovery. A decrease in locomotor activity and an upregulation of GFAP was observed concomitant to a persistent decrease in risk-avoidance despite thermal, short-term memory, and iba-1 measurements recovery 14-days post-impact. Overall, these results indicate that low magnitude subconcussive impacts can produce latent thermal, behavioral, and histological disturbances uncharacteristic for a head injury model suggestive of a biomechanical threshold of altered pathodynamics that fail to fully recover after 14 days.

No description available.

No description available.

No description available.

No description available.

No description available.

No description available.

No description available.

No description available.

<p><strong>Purpose:</strong> Microglia are the innate immune cells of the central nervous system. Activated microglia release nitric oxide, glutamate, and superoxide radicals, which are harmful to retinal ganglion cells (RGCs). They may also benefit surviving cells by removing toxic cellular debris or by secretion of neurotrophic factors. The paradoxical role of microglia remains controversial because the nature and time-course of the injury that determines whether microglia acquire a neuroprotective or pro-inflammatory phenotype is unknown. HAPI cells are an immortalized microglial cell line, whose phenotype can be manipulated <em>in vitro</em>. It is my HYPOTHESIS that pharmacological manipulation of microglia to acquire either a pro-inflammatory or pro-survival phenotype will exacerbate neuronal cell death or enhance neuronal survival after injury, respectively.</p> <p><strong>Method:</strong> Lipopolysaccharides (LPS) were used to hyper-stimulate the HAPI cells and minocycline to maintain the HAPI cells in a quiescent state. Prior to the experiments, the HAPI cells were labelled with Wheat Germ Agglutinin conjugated to Texas Red. The HAPI cells were cultured and exposed to minocycline (10 µg/mL for 1 hour) or LPS (1 µg/mL for 24 hours). Sprague-Dawley rats then recieved intraocular (30,000 cells) or tail vein (5 million cells) injections of either the minocycline treated HAPI cells or the LPS treated HAPI cells and an optic nerve crush. Retinas were examined at 4-14 days later and the number of surviving RGCs will be determined by Brn3a labelling of RGCs. BM88 antibody labelling was done to determine the severity of the injury and to determine molecular changes after neuroinflammation.</p> <p><strong>Results: </strong>Injection of untreated HAPI cells resulted in the greater loss of RGCs early after ONC when injected into the vitreous and later after ONC when injected into the tail vein. LPS activated HAPI cells injected into the vitreous resulted in greater RGC loss with and without injury. When injected into the tail vein with ONC there was no loss of RGCs 4 days after ONC but later there was greater loss of RGCs. Minocycline treated HAPI cells injected into the vitreous resulted in greater RGC survival than when untreated HAPI cells were injected. However, when injected into the tail vein with ONC there was greater loss of RGCs. There was also BM88 down regulation after injury and this was more pronounced after HAPI cell injection.</p> <p><strong>Conclusion:</strong> Neuroprotection or cytotoxicity of microglia depends on the type of activation, time course of the injury, and if the microglia act on the axon or cell body of the retinal ganglion cell.</p> / Doctor of Philosophy (PhD)