After receiving my Bachelors (2006) and Masters (2010) degrees at the University of Wisconsin – Milwaukee, I obtained my PhD at Southern Illinois University in 2013. My current research focuses on the central nervous systems response to insult.
I am interested in understanding the complex cellular and molecular interactions that comprise the neuroinflammatory response to neural injury in an effort to develop therapeutic treatment options that produce the most optimal response to multiple types of neural insult and other neurobiological disorders. The World Health Organization reports that neurological disorders are one of the greatest threats to public health. Of the hundreds of these disorders, some of the most common are traumatic brain injury, stroke, and degenerative disorders. Although these disorders are initiated through different causes, the common underlying factor in all of these neurodegenerative diseases is neuroinflammation. The acute response is characterized by glial cell activation, oxidative stress, and edema, all of which lead to increased tissue damage. Chronic neuroinflammation is a sustained, self-perpetuating response that persists long after the onset of neural insult. There is a complex interaction between resident immune cells like microglia and astrocytes and infiltrating immune cells including neutrophils, macrophages, and T lymphocytes. This complicated response to neural injury is a defense mechanism to remove harmful agents and promote recovery, but when over active, it can contribute to further damage. My current objective is to identify the underlying mechanisms of the neuroinflammatory response in multiple different animal models of injury and neurobiological disorders. Ultimately my goal is to steer a group that is running preclinical trials on cellular and molecular compounds designed to reduce the harmful features of the neuroinflammatory response but to harness the beneficial aspects.
Honors & Awards
NRSA Training Fellowship, National Institute of Health (Fall 2014-Fall 2017)
Bachelor, University of Wisconsin - Milwaukee (2006)
Master of Science, University of Wisconsin Milwaukee (2010)
Doctor of Philosophy, Southern Illinois Univ-Carbondale (2013)
Marion Buckwalter, Postdoctoral Faculty Sponsor
Neurotoxic reactive astrocytes are induced by activated microglia.
2017; 541 (7638): 481-487
Reactive astrocytes are strongly induced by central nervous system (CNS) injury and disease, but their role is poorly understood. Here we show that a subtype of reactive astrocytes, which we termed A1, is induced by classically activated neuroinflammatory microglia. We show that activated microglia induce A1 astrocytes by secreting Il-1α, TNF and C1q, and that these cytokines together are necessary and sufficient to induce A1 astrocytes. A1 astrocytes lose the ability to promote neuronal survival, outgrowth, synaptogenesis and phagocytosis, and induce the death of neurons and oligodendrocytes. Death of axotomized CNS neurons in vivo is prevented when the formation of A1 astrocytes is blocked. Finally, we show that A1 astrocytes are abundant in various human neurodegenerative diseases including Alzheimer's, Huntington's and Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis. Taken together these findings help to explain why CNS neurons die after axotomy, strongly suggest that A1 astrocytes contribute to the death of neurons and oligodendrocytes in neurodegenerative disorders, and provide opportunities for the development of new treatments for these diseases.
View details for DOI 10.1038/nature21029
View details for PubMedID 28099414
View details for PubMedCentralID PMC5404890
A behavioral and histological comparison of fluid percussion injury and controlled cortical impact injury to the rat sensorimotor cortex
BEHAVIOURAL BRAIN RESEARCH
2015; 294: 254-263
Our primary goal was to evaluate the behavioral and histological outcome of fluid percussion injury (FPI) and cortical contusion injury (CCI) to the sensorimotor cortex (SMC). The SMC has been used to evaluate neuroplasticity following CCI, but has not been extensively examined with FPI. In both the CCI and FPI models, a mechanical force of 4mm in diameter was applied over the SMC, allowing for a direct comparison to measure the relative rates of histology and recovery of function in these models. Gross behavioral deficits were found on the sensory task (tactile adhesive removal task) and multiple motor assessments (forelimb asymmetry task, forelimb placing task, and rotorod). These sensorimotor deficits occurred in the absence of cognitive deficits in the water maze. The CCI model creates focal damage with a localized injury wheras the FPI model creates a more diffuse injury causing widespread damage. Both behavioral and histological deficits ensued following both models of injury to the SMC. The neuroplastic changes and ease at which damage to this area can be measured behaviorally make this an excellent location to assess traumatic brain injury (TBI) treatments. No injury model can completely mimic the full spectrum of human TBI and any potential treatments should be validated across both focal and diffuse injury models. Both of these injury models to the SMC produce severe and enduring behavioral deficits, which are ideal for evaluating treatment options.
View details for DOI 10.1016/j.bbr.2015.08.007
View details for Web of Science ID 000361934000029
View details for PubMedID 26275924
View details for PubMedCentralID PMC4580137
A Combination Therapy of Nicotinamide and Progesterone Improves Functional Recovery following Traumatic Brain Injury
JOURNAL OF NEUROTRAUMA
2015; 32 (11): 765-779
Neuroprotection, recovery of function, and gene expression were evaluated in an animal model of traumatic brain injury (TBI) after a combination treatment of nicotinamide (NAM) and progesterone (Prog). Animals received a cortical contusion injury over the sensorimotor cortex, and were treated with either Vehicle, NAM, Prog, or a NAM/Prog combination for 72 h and compared with a craniotomy only (Sham) group. Animals were assessed in a battery of behavioral, sensory, and both fine and gross motor tasks, and given histological assessments at 24 h post-injury to determine lesion cavity size, degenerating neurons, and reactive astrocytes. Microarray-based transcriptional profiling was used to determine treatment-specific changes on gene expression. Our results confirm the beneficial effects of treatment with either NAM or Prog, demonstrating significant improvements in recovery of function and a reduction in lesion cavitation, degenerating neurons, and reactive astrocytes 24 h post-injury. The combination treatment of NAM and Prog led to a significant improvement in both neuroprotection at 24 h post-injury and recovery of function in sensorimotor related tasks when compared with individual treatments. The NAM/Prog-treated group was the only treatment group to show a significant reduction of cortical loss 24 h post-injury. The combination appears to affect inflammatory and immune processes, reducing expression of a significant number of genes in both pathways. Further preclinical trials using NAM and Prog as a combination treatment should be conducted to identify the window of opportunity, determine the optimal duration of treatment, and evaluate the combination in other pre-clinical models of TBI.
View details for DOI 10.1089/neu.2014.3530
View details for Web of Science ID 000363980700002
View details for PubMedID 25313690
View details for PubMedCentralID PMC4449633
Cerebellar dentate nuclei lesions alter prefrontal cortex dendritic spine morphology
2014; 1544: 15-24
Anatomical tracing studies in primates have revealed neural tracts from the cerebellar dentate nuclei to prefrontal cortex, implicating a cerebellar role in nonmotor processes. Experiments in rats examining the functional role of this cerebellothalamocortical pathway have demonstrated the development of visuospatial and motivational deficits following lesions of the dentate nuclei, in the absence of motor impairment. These behavioral deficits possibly occur due to structural modifications of the cerebral cortex secondary to loss of cerebellar input. The current study characterized morphological alterations in prefrontal cortex important for visuospatial and motivational processes following bilateral cerebellar dentate nuclei lesions. Rats received either bilateral electrolytic cerebellar dentate nuclei lesions or sham surgery followed by a 30-day recovery. Randomly selected Golgi-impregnated neurons in prefrontal cortex were examined for analysis. Measures of branch length and spine density revealed no differences between lesioned and sham rats in either apical or basilar arbors; however, the proportion of immature to mature spines significantly decreased in lesioned rats as compared to sham controls, with reductions of 33% in the basilar arbor and 28% in the apical arbor. Although expected pruning of branches and spines did not occur, the results are consistent with the hypothesis that cerebellar lesions influence prefrontal morphology and support the possibility that functional deficits following cerebellar dentate nuclei lesions are related to prefrontal morphological alteration.
View details for DOI 10.1016/j.brainres.2013.11.032
View details for Web of Science ID 000330494200002
View details for PubMedID 24321616
Behavior Modification After Inactivation of Cerebellar Dentate Nuclei
2012; 126 (4): 551-562
Effort-based decision making occurs when subjects are given a choice between a reward available at a high response cost and a reward available at a low response cost and is altered in individuals with disorders such as autism or particular patterns of brain injury. The current study explored the relationship between effort-based decision making and reinforcement characteristics in the T maze. This was done using both normal animals and animals with bilateral inactivation of the cerebellar dentate nuclei. Rats chose between alternatives in which one arm contained high-density reinforcement (HR) and the other arm contained low-density reinforcement (LR). During training, the HR arm was obstructed and the point at which the animal no longer worked for reinforcement (breaking point) was determined. The cerebellar dentate nuclei were then transiently inactivated and once again breaking points were assessed. The results indicated that inactivation of the dentate nucleus disrupted effort-based decision making. Additionally, altering both the palatability and the magnitude of the reinforcement were assessed in an attempt to reestablish the original preinactivation breaking point. It was hypothesized that an increase in the strength or magnitude of the reinforcement would promote an increase in the breaking point of the animal even when the cerebellum was inactivated. The results indicated that with both strategies animals effectively reestablished original breaking points. The results of this study will inform the current literature regarding the modification of behavior after brain injury and further the understanding of the behavioral deficits associated with cerebellar dysfunction.
View details for DOI 10.1037/a0028701
View details for Web of Science ID 000306766100006
View details for PubMedID 22845704
Vitamins and nutrients as primary treatments in experimental brain injury: Clinical implications for nutraceutical therapies
2016; 1640: 114-129
With the numerous failures of pharmaceuticals to treat traumatic brain injury in humans, more researchers have become interested in combination therapies. This is largely due to the multimodal nature of damage from injury, which causes excitotoxicity, oxidative stress, edema, neuroinflammation and cell death. Polydrug treatments have the potential to target multiple aspects of the secondary injury cascade, while many previous therapies focused on one particular aspect. Of specific note are vitamins, minerals and nutrients that can be utilized to supplement other therapies. Many of these have low toxicity, are already FDA approved and have minimal interactions with other drugs, making them attractive targets for therapeutics. Over the past 20 years, interest in supplementation and supraphysiologic dosing of nutrients for brain injury has increased and indeed many vitamins and nutrients now have a considerable body of the literature backing their use. Here, we review several of the prominent therapies in the category of nutraceutical treatment for brain injury in experimental models, including vitamins (B2, B3, B6, B9, C, D, E), herbs and traditional medicines (ginseng, Gingko biloba), flavonoids, and other nutrients (magnesium, zinc, carnitine, omega-3 fatty acids). While there is still much work to be done, several of these have strong potential for clinical therapies, particularly with regard to polydrug regimens. This article is part of a Special Issue entitled SI:Brain injury and recovery.
View details for DOI 10.1016/j.brainres.2015.12.030
View details for Web of Science ID 000378447600009
View details for PubMedID 26723564
View details for PubMedCentralID PMC4870112
Effect of Traumatic Brain Injury, Erythropoietin, and Anakinra on Hepatic Metabolizing Enzymes and Transporters in an Experimental Rat Model.
2015; 17 (5): 1255-1267
In contrast to considerable data demonstrating a decrease in cytochrome P450 (CYP) activity in inflammation and infection, clinically, traumatic brain injury (TBI) results in an increase in CYP and UDP glucuronosyltransferase (UGT) activity. The objective of this study was to determine the effects of TBI alone and with treatment with erythropoietin (EPO) or anakinra on the gene expression of hepatic inflammatory proteins, drug-metabolizing enzymes, and transporters in a cortical contusion impact (CCI) injury model. Microarray-based transcriptional profiling was used to determine the effect on gene expression at 24 h, 72 h, and 7 days post-CCI. Plasma cytokine and liver protein concentrations of CYP2D4, CYP3A1, EPHX1, and UGT2B7 were determined. There was no effect of TBI, TBI + EPO, or TBI + anakinra on gene expression of the inflammatory factors shown to be associated with decreased expression of hepatic metabolic enzymes in models of infection and inflammation. IL-6 plasma concentrations were increased in TBI animals and decreased with EPO and anakinra treatment. There was no significant effect of TBI and/or anakinra on gene expression of enzymes or transporters known to be involved in drug disposition. TBI + EPO treatment decreased the gene expression of Cyp2d4 at 72 h with a corresponding decrease in CYP2D4 protein at 72 h and 7 days. CYP3A1 protein was decreased at 24 h. In conclusion, EPO treatment may result in a significant decrease in the metabolism of Cyp-metabolized drugs. In contrast to clinical TBI, there was not a significant effect of experimental TBI on CYP or UGT metabolic enzymes.
View details for DOI 10.1208/s12248-015-9792-y
View details for PubMedID 26068867
View details for PubMedCentralID PMC4540723
- The effect of nicotinamide on gene expression in a traumatic brain injury model FRONTIERS IN NEUROSCIENCE 2013; 7
Comparison of the effects of erythropoietin and anakinra on functional recovery and gene expression in a traumatic brain injury model.
Frontiers in pharmacology
2013; 4: 129-?
The goal of this study was to compare the effects of two inflammatory modulators, erythropoietin (EPO) and anakinra, on functional recovery and brain gene expression following a cortical contusion impact (CCI) injury. Dosage regimens were designed to provide serum concentrations in the range obtained with clinically approved doses. Functional recovery was assessed using both motor and spatial learning tasks and neuropathological measurements conducted in the cortex and hippocampus. Microarray-based transcriptional profiling was used to determine the effect on gene expression at 24 h, 72 h, and 7 days post-CCI. Ingenuity Pathway Analysis was used to evaluate the effect on relevant functional categories. EPO and anakinra treatment resulted in significant changes in brain gene expression in the CCI model demonstrating acceptable brain penetration. At all three time points, EPO treatment resulted in significantly more differentially expressed genes than anakinra. For anakinra at 24 h and EPO at 24 h, 72 h, and 7 days, the genes in the top 3 functional categories were involved in cellular movement, inflammatory response and cell-to-cell signaling. For EPO, the majority of the genes in the top 10 canonical pathways identified were associated with inflammatory and immune signaling processes. This was true for anakinra only at 24 h post-traumatic brain injury (TBI). The immunomodulation effects of EPO and anakinra did not translate into positive effects on functional behavioral and lesion studies. Treatment with either EPO or anakinra failed to induce significant beneficial effects on recovery of function or produce any significant effects on the prevention of injury induced tissue loss at 30 days post-injury. In conclusion, treatment with EPO or anakinra resulted in significant effects on gene expression in the brain without affecting functional outcome. This suggests that targeting these inflammatory processes alone may not be sufficient for preventing secondary injuries after TBI.
View details for DOI 10.3389/fphar.2013.00129
View details for PubMedID 24151467
View details for PubMedCentralID PMC3798024
- The use of nicotinamide as a treatment for experimental brain injury and stroke: A review and evaluation Clinical Pharmacology and Biopharmaceuticals 2013
Introgression of Brown Norway Chromosome 13 Improves Visual Spatial Memory in the Dahl S Rat
2010; 40 (1): 76-84
The present study was conducted in an effort to evaluate whether chromosomal substitution can repair impaired exploration learning and memory. It has previously been observed that Dahl salt-sensitive (SS) rodents exhibit impaired cognitive function along with abnormal physiological responses to muscle stimulation. Introgression of Brown Norway chromosome (13(BN)) has been found to restore normal physiological processes in SS animals. However, the effect of chromosomal substitution on cognitive performance has not been explored. It was hypothesized that 13(BN) also rescues cognitive impairments in these animals. Visual spatial learning and cognitive flexibility were evaluated using the Morris water maze (MWM) and the T-maze. This manipulation is effective in rescuing impaired task acquisition, but not perseveration observed in the SS animal. These animals may represent a natural animal model in which to isolate genetic information responsible for learning and memory function.
View details for DOI 10.1007/s10519-009-9296-6
View details for Web of Science ID 000273083000010
View details for PubMedID 19763809