Gulf war toxicant-induced effects on the hippocampal dendritic arbor are reversed by treatment with a Withania somnifera extract.

Gulf War Illness (GWI) is a multi-symptom disorder that manifests with fatigue, sleep disturbances, mood-cognition pathologies, and musculoskeletal symptoms. GWI affects at least 25% of the military personnel that served in Operations Desert Shield and Desert Storm from 1990 to 1991. We modeled Gulf War toxicant exposure in C57BL/6J mice by combined exposure to pyridostigmine bromide (an anti-sarin drug), chlorpyrifos (an organophosphate insecticide), and DEET (an insect repellent) for 10 days followed by oral treatment with Withania somnifera root extract for 21 days beginning at 12 weeks post-exposure. W. somnifera, commonly referred to as ashwagandha, has been used in traditional Ayurvedic medicine for centuries to improve memory and reduce inflammation, and its roots contain bioactive molecules which share functional groups with modern pain, cancer, and anti-inflammatory drugs. Previously, we observed that GWI mice displayed chronic reductions in dendritic arbor and loss of spines in granule cells of the dentate gyrus of the hippocampus at 14 weeks post-exposure. Here, we examined the effects of treatment with W. somnifera root extract on chronic dendrite and spine morphology in dentate granule cells of the mouse hippocampus following Gulf War toxicant exposure. GWI mice showed approximately 25% decreases in dendritic length (p < 0.0001) and overall dendritic spine density with significant reductions in thin and mushroom spines. GWI mice treated with the Ayurvedic W. somnifera extract exhibited dendritic lengths and spine densities near normal levels. These findings demonstrate the efficacy of the Ayurvedic treatment for neuroprotection following these toxic exposures. We hope that the extract and the neuronal processes influenced will open new avenues of research regarding treatment of Gulf War Illness and neurodegenerative disorders.

Systematic Review of Post-Traumatic Parkinsonism, an Emerging Parkinsonian Disorder Among Survivors of Traumatic Brain Injury.

This systematic review focuses on an increasing subset of traumatic brain injury (TBI) survivors who develop post-traumatic parkinsonism (PTP), characterized by slowness of movement (bradykinesia), rigidity (stiffness), postural instability, and resting tremors caused by obstruction or damage to deep brain structures of the basal ganglia. PTP is rare, and one hypothesis to explain PTP rarity is that TBIs severe enough to affect deep brain structures are often lethal; however, with increasing survivability of TBIs, these numbers are expected to increase. The goal of this review is to raise awareness of an expected global increase of a subgroup of TBI patients who are treatment responsive and report therapeutic results aiding providers in diagnosing, educating, and treating PTP patients. Literature over the past 100 years was considered, and 44,663 peer-reviewed articles were identified. Inclusion criteria required a clinical indication of parkinsonian signs and TBI. Twenty-six case reports were ultimately included from which 36 individual patient data points were extracted for this review. Between 1980 and 2010, there has been an increase in reporting of PTP decade after decade. Forty-seven percent of PTP cases have 1-6 months of latency to symptom onset, and 83% of cases were male. PTP can occur with or without presence of brain lesions, and the most common type of injuries that cause PTP are motor vehicle accidents followed by falls. PTP patients are responsive to surgery or medication treatments. Further detail on PTP symptomology, treatment responsiveness, and injury types is provided.

MCC950 Attenuates Microglial NLRP3-Mediated Chronic Neuroinflammation and Memory Impairment in a Rat Model of Repeated Low-Level Blast Exposure.

Blast-induced traumatic brain injury is typically regarded as a signature medical concern for military personnel who are exposed to explosive devices in active combat zones. However, soldiers as well as law enforcement personnel may be repeatedly exposed to low-level blasts during training sessions with heavy weaponries as part of combat readiness. Service personnel who sustain neurotrauma from repeated low-level blast (rLLB) exposure do not display overt pathological symptoms immediately but rather develop mild symptoms including cognitive impairments, attention deficits, mood changes, irritability, and sleep disturbances over time. Recently, we developed a rat model of rLLB by applying controlled low-level blast pressures (≤ 70 kPa) repeated five times successively to mimic the pressures experienced by service members. Using this model, we assessed anxiety-like symptoms, motor coordination, and short-term memory as a function of time. We also investigated the role of the NLRP3 inflammasome, a complex involved in chronic microglial activation and pro-inflammatory cytokine interleukin (IL)-1ß release, in rLLB-induced neuroinflammation. NLRP3 and caspase-1 protein expression, microglial activation, and IL-1ß release were examined as factors likely contributing to these neurobehavioral changes. Animals exposed to rLLB displayed acute and chronic short-term memory impairments and chronic anxiety-like symptoms accompanied by increased microglial activation, NLRP3 expression, and IL-1ß release. Treatment with MCC950, an NLRP3 inflammasome complex inhibitor, suppressed microglial activation, reduced NLRP3 expression and IL-1ß release, and improved short-term memory deficits after rLLB exposure. Collectively, this study demonstrates that rLLB induces chronic neurobehavioral and neuropathological changes by increasing NLRP3 inflammasome protein expression followed by cytokine IL-1ß release.

Gulf War toxicant-induced reductions in dendritic arbors and spine densities of dentate granule cells are improved by treatment with a Nrf2 activator.

Gulf War Illness (GWI) is a chronic multi-symptom disorder affecting approximately 30 % of Veterans deployed to the Persian Gulf from 1990 to 91. GWI encompasses a wide spectrum of symptoms which frequently include neurological problems such as learning and memory impairments, mood disorders, and an increased incidence of neurodegenerative disorders. Combined exposure to both reversible and irreversible acetylcholinesterase (AChE) inhibitors has been identified as a likely risk factor for GWI. It is possible that the exposures affected connectivity in the brain, and it was also unknown whether this could benefit from treatment. We assessed chronic changes in dendritic architecture in granule cells of the dentate gyrus following exposure to pyridostigmine bromide (PB, 0.7 mg/kg), chlorpyrifos (CPF, 12.5 mg/kg), and N,N-diethyl-m-toluamide (DEET, 7.5 mg/kg) in male C57Bl/6J mice. We also evaluated the therapeutic effects of dietary administration for eight weeks of 1 % tert-butylhydroquinone (tBHQ), a Nrf2 activator, on long-term neuronal morphology. We found that Gulf War toxicant exposure resulted in reduced dendritic length and branching as well as overall spine density in dentate granule cells at 14 weeks post-exposure and that these effects were ameliorated by treatment with tBHQ. These findings indicate that Gulf War toxicant exposure results in chronic changes to dentate granule cell morphology and that modulation of neuroprotective transcription factors such as Nrf2 may improve long-term neuronal health in the hippocampus.

Cognitive and Cellular Effects of Combined Organophosphate Toxicity and Mild Traumatic Brain Injury.

Traumatic brain injury (TBI) is considered the most common neurological disorder among people under the age of 50. In modern combat zones, a combination of TBI and organophosphates (OP) can cause both fatal and long-term effects on the brain. We utilized a mouse closed-head TBI model induced by a weight drop device, along with OP exposure to paraoxon. Spatial and visual memory as well as neuron loss and reactive astrocytosis were measured 30 days after exposure to mild TBI (mTBI) and/or paraoxon. Molecular and cellular changes were assessed in the temporal cortex and hippocampus. Cognitive and behavioral deficits were most pronounced in animals that received a combination of paraoxon exposure and mTBI, suggesting an additive effect of the insults. Neuron survival was reduced in proximity to the injury site after exposure to paraoxon with or without mTBI, whereas in the dentate gyrus hilus, cell survival was only reduced in mice exposed to paraoxon prior to sustaining a mTBI. Neuroinflammation was increased in the dentate gyrus in all groups exposed to mTBI and/or to paraoxon. Astrocyte morphology was significantly changed in mice exposed to paraoxon prior to sustaining an mTBI. These results provide further support for assumptions concerning the effects of OP exposure following the Gulf War. This study reveals additional insights into the potentially additive effects of OP exposure and mTBI, which may result in more severe brain damage on the modern battlefield.

Repetitive mild TBI causes pTau aggregation in nigra without altering preexisting fibril induced Parkinson's-like pathology burden.

Population studies have shown that traumatic brain injury (TBI) is associated with an increased risk for Parkinson's disease (PD) and among U.S. Veterans with a history of TBI this risk is 56% higher. The most common type of TBI is mild (mTBI) and often occurs repeatedly among athletes, military personnel, and victims of domestic violence. PD is classically characterized by deficits in fine motor movement control resulting from progressive neurodegeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) midbrain region. This neurodegeneration is preceded by the predictable spread of characteristic alpha synuclein (αSyn) protein inclusions. Whether repetitive mTBI (r-mTBI) can nucleate PD pathology or accelerate prodromal PD pathology remains unknown. To answer this question, an injury device was constructed to deliver a surgery-free r-mTBI to rats and human-like PD pathology was induced by intracranial injection of recombinant αSyn preformed fibrils. At the 3-month endpoint, the r-mTBI caused encephalomalacia throughout the brain reminiscent of neuroimaging findings in patients with a history of mTBI, accompanied by astrocyte expansion and microglial activation. The pathology associated most closely with PD, which includes dopaminergic neurodegeneration in the SNpc and Lewy body-like αSyn inclusion burden in the surviving neurons, was not produced de novo by r-mTBI nor was the fibril induced preexisting pathology accelerated. r-mTBI did however cause aggregation of phosphorylated Tau (pTau) protein in nigra of rats with and without preexisting PD-like pathology. pTau aggregation was also found to colocalize with PFF induced αSyn pathology without r-mTBI. These findings suggest that r-mTBI induced pTau aggregate deposition in dopaminergic neurons may create an environment conducive to αSyn pathology nucleation and may add to preexisting proteinaceous aggregate burden.

Sidestream Smoke Affects Dendritic Complexity and Astrocytes After Model Mild Closed Head Traumatic Brain Injury.

Mild traumatic brain injuries can have long-term consequences that interfere with the life of the patient and impose a burden on our health care system. Oxidative stress has been identified as a contributing factor for the progression of neurodegeneration following TBI. A major source of oxidative stress for many veterans is cigarette smoking and second-hand smoke, which has been shown to have an effect on TBI recovery. To examine the potential influences of second-hand smoke during recovery from TBI, we utilized a mouse model of closed head injury, followed by repeated exposure to cigarette smoke and treatment with a neuroprotective antioxidant. We found that neither the mild injuries nor the smoke exposure produced axonal damage detectable with amino cupric silver staining. However, complexity in the dendritic arbors was significantly reduced after mild TBI plus smoke exposure. In the hippocampus, there were astrocytic responses, including Cyp2e1 upregulation, after the injury and tobacco smoke insult. This study provides useful context for the importance of lifestyle changes, such as reducing or eliminating cigarette smoking, during recovery from TBI.

Ketogenic Diet as a potential treatment for traumatic brain injury in mice.

Traumatic brain injury (TBI) is a brain dysfunction without present treatment. Previous studies have shown that animals fed ketogenic diet (KD) perform better in learning tasks than those fed standard diet (SD) following brain injury. The goal of this study was to examine whether KD is a neuroprotective in TBI mouse model. We utilized a closed head injury model to induce TBI in mice, followed by up to 30 days of KD/SD. Elevated levels of ketone bodies were confirmed in the blood following KD. Cognitive and behavioral performance was assessed post injury and molecular and cellular changes were assessed within the temporal cortex and hippocampus. Y-maze and Novel Object Recognition tasks indicated that mTBI mice maintained on KD displayed better cognitive abilities than mTBI mice maintained on SD. Mice maintained on SD post-injury demonstrated SIRT1 reduction when compared with uninjured and KD groups. In addition, KD management attenuated mTBI-induced astrocyte reactivity in the dentate gyrus and decreased degeneration of neurons in the dentate gyrus and in the cortex. These results support accumulating evidence that KD may be an effective approach to increase the brain's resistance to damage and suggest a potential new therapeutic strategy for treating TBI.

Pyridostigmine bromide, chlorpyrifos, and DEET combined Gulf War exposure insult depresses mitochondrial function in neuroblastoma cells.

Gulf War Illness (GWI) is defined by the Centers for Disease Control and Prevention (CDC) as a multi-symptom illness having at least one symptom from two of three factors, which include: fatigue, mood-cognition problems, and musculoskeletal disorders. The cluster of long-term symptoms is unique to military personnel from coalition countries including United States, Australia, and the United Kingdom that served in Operation Desert Storm from 1990 to 1991. Reporting of these symptoms is much lower among soldiers deployed in other parts of the world like Bosnia during the same time period. The exact cause of GWI is unknown, but combined exposure to N,N-diethyl-m-toluamide (DEET), organophosphates like chlorpyrifos (CPF), and pyridostigmine bromide (PB), has been hypothesized as a potential mechanism. Mitochondrial dysfunction is known to occur in most neurodegenerative diseases that share symptoms with GWI and has therefore been implicated in GWI. Although exposure to these and other toxicants continues to be investigated as potential causes of GWI, their combined impact on mitochondrial physiology remains unknown. In this study, the effects of combined GWI toxicant exposure on mitochondrial function were determined in a commonly used and readily available immortalized cell line (N2a), whose higher rate of oxygen consumption resembles that of highly metabolic neurons in vivo. We report that combined exposure containing pesticide CPF 71 µM, insect repellants DEET 78 µM, and antitoxins PB 19 µM, causes profound mitochondrial dysfunction after a 4-h incubation resulting in decreased mitochondrial respiratory states in the absence of proapoptotic signaling, proton leak, or significant increase in reactive oxygen species production.

Acute gene expression changes in the mouse hippocampus following a combined Gulf War toxicant exposure.

AIMS: Approximately 30% of the nearly 700,000 Veterans who were deployed to the Gulf War from 1990 to 1991 have reported experiencing a variety of symptoms including difficulties with learning and memory, depression and anxiety, and increased incidence of neurodegenerative diseases. Combined toxicant exposure to acetylcholinesterase (AChE) inhibitors has been studied extensively as a likely risk factor. In this study, we modeled Gulf War exposure in male C57Bl/6J mice with simultaneous administration of three chemicals implicated as exposure hazards for Gulf War Veterans: pyridostigmine bromide, the anti-sarin prophylactic; chlorpyrifos, an organophosphate insecticide; and the repellant N,N-diethyl-m-toluamide (DEET). MAIN METHODS: Following two weeks of daily exposure, we examined changes in gene expression by whole transcriptome sequencing (RNA-Seq) with hippocampal isolates. Hippocampal-associated spatial memory was assessed with a Y-maze task. We hypothesized that genes important for neuronal health become dysregulated by toxicant-induced damage and that these detrimental inflammatory gene expression profiles could lead to chronic neurodegeneration. KEY FINDINGS: We found dysregulation of genes indicating a pro-inflammatory response and downregulation of genes associated with neuronal health and several important immediate early genes (IEGs), including Arc and Egr1, which were both reduced approximately 1.5-fold. Mice exposed to PB + CPF + DEET displayed a 1.6-fold reduction in preference for the novel arm, indicating impaired spatial memory. SIGNIFICANCE: Differentially expressed genes observed at an acute timepoint may provide insight into the pathophysiology of Gulf War Illness and further explanations for chronic neurodegeneration after toxicant exposure.

Gene Expression Changes in a Model Neuron Cell Line Exposed to Autoantibodies from Patients with Traumatic Brain Injury and/or Type 2 Diabetes.

Traumatic brain injury and adult type 2 diabetes mellitus are each associated with the late occurrence of accelerated cognitive decline and Parkinson's disease through unknown mechanisms. Previously, we reported increased circulating agonist autoantibodies targeting the 5-hydroxytryptamine 2A receptor in plasma from subsets of Parkinson's disease, dementia, and diabetic patients suffering with microvascular complications. Here, we use a model neuron, mouse neuroblastoma (N2A) cell line, to test messenger RNA expression changes following brief exposure to traumatic brain injury and/or type 2 diabetes mellitus plasma harboring agonist 5-hydroxytryptamine 2A receptor autoantibodies. We now report involvement of the mitochondrial dysfunction pathway and Parkinson's disease pathways in autoantibody-induced gene expression changes occurring in neuroblastoma cells. Functional gene categories upregulated significantly included cell death, cytoskeleton-microtubule function, actin polymerization or depolymerization, regulation of cell oxidative stress, mitochondrial function, immune function, protein metabolism, and vesicle function. Gene categories significantly downregulated included microtubule function, cell adhesion, neurotransmitter release, dopamine metabolism synaptic plasticity, maintenance of neuronal differentiation, mitochondrial function, and cell signaling. Taken together, these results suggest that agonist 5-hydroxytryptamine receptor autoantibodies (which increase in Parkinson's disease and other forms of neurodegeneration) mediate a coordinating program of gene expression changes in a model neuron which predispose to neuro-apoptosis and are linked to human neurodegenerative diseases pathways.

Sleep Deprivation, a Link Between Post-Traumatic Stress Disorder and Alzheimer's Disease.

An estimated 5 million Americans are living with Alzheimer's disease (AD), and there is also a significant impact on caregivers, with an additional 16 million Americans providing unpaid care for individuals with AD and other dementias. These numbers are projected to increase in the coming years. While AD is still without a cure, continued research efforts have led to better understanding of pathology and potential risk factors that could be exploited to slow disease progression. A bidirectional relationship between sleep deprivation and AD has been suggested and is well supported by both human and animal studies. Even brief episodes of inadequate sleep have been shown to cause an increase in amyloidß and tau proteins, both well-established contributors toAD pathology. Sleep deprivation is also the most common consequence of post-traumatic stress disorder (PTSD). Patients with PTSD frequently present with sleep disturbances and also develop dementia at twice the rate of the general population accounting for a disproportionate representation of AD among U.S. Veterans. The goal of this review is to highlight the relationship triad between sleep deprivation, AD, and PTSD as well as their impact on molecular mechanisms driving AD pathology.

Dendritic arbor complexity and spine density changes after repetitive mild traumatic brain injury and neuroprotective treatments.

Traumatic brain injury has been described as the signature affliction of recent military conflicts and repetitive TBIs, particularly associated with military and athletic activities, typically result in more severe clinical effects. The majority of TBIs are mild, but they can result in long term cognitive deficits for which there is no effective treatment. One of the most significant deficits observed in TBI patients is memory loss, which suggests that TBI can induce pathological changes within the hippocampus. tert-butylhydroquinone (tBHQ) and pioglitazone activate the Nrf2 and PPAR-γ transcription factors, respectively, and both have been shown to be neuroprotective in model systems. We examined the morphological changes within the hippocampus following repetitive mild TBI and simultaneous treatment with both factors. We utilized a closed head injury mouse model with five injuries over 5 weeks. Our results showed marked morphological changes among the dendrites and dendritic spines of the neurons of the dentate gyrus of the hippocampus. We observed decreases in overall dendritic length, as well as in the quantity and density of dendritic spines. Our treatment partially ameliorated these effects, suggesting that the Nrf2 and PPAR-γ transcription factors may be important targets for future drug development in the treatment of TBI in humans.

Repetitive Mild Traumatic Brain Injury and Transcription Factor Modulation.

The worldwide incidence of traumatic brain injury (TBI) is ∼0.5% per year and the frequency is significantly higher among military personnel and athletes. Repetitive TBIs are associated with military and athletic activities, and typically involve more severe consequences. The majority of TBIs are mild; however, these still can result in long-term cognitive deficits, and there is currently no effective treatment. tert-Butylhydroquinone (tBHQ) and pioglitazone can activate the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and peroxisome proliferator-activated receptor-gamma (PPAR-γ) transcription factors, respectively, and each has been shown to be neuroprotective in various model systems. We examined behavioral and gene expression changes after repetitive mild TBI followed by simultaneous treatment with both factors. We used a repetitive closed head injury of mice involving five injuries with a 1-week interval between each TBI. We found that memory performance was significantly reduced by the injuries, unless the TBIs were followed by the tBHQ and pioglitazone administrations. Certain genes; for example, growth hormone and osteopontin, were downregulated by the injury, and this was reversed by the treatment, whereas other genes; for example, a tumor necrosis factor receptor, were upregulated by the injury and restored if the post-injury treatment was administered. Analysis of gene expression levels affected by the injury and/or the treatment point to potential mechanisms that could be exploited therapeutically.

Biological links between traumatic brain injury and Parkinson's disease.

Parkinson's Disease (PD) is a progressive neurodegenerative disorder with no cure. Clinical presentation is characterized by postural instability, resting tremors, and gait problems that result from progressive loss of A9 dopaminergic neurons in the substantia nigra pars compacta. Traumatic brain injury (TBI) has been implicated as a risk factor for several neurodegenerative diseases, but the strongest evidence is linked to development of PD. Mild TBI (mTBI), is the most common and is defined by minimal, if any, loss of consciousness and the absence of significant observable damage to the brain tissue. mTBI is responsible for a 56% higher risk of developing PD in U.S. Veterans and the risk increases with severity of injury. While the mounting evidence from human studies suggests a link between TBI and PD, fundamental questions as to whether TBI nucleates PD pathology or accelerates PD pathology in vulnerable populations remains unanswered. Several promising lines of research point to inflammation, metabolic dysregulation, and protein accumulation as potential mechanisms through which TBI can initiate or accelerate PD. Amyloid precursor protein (APP), alpha synuclein (α-syn), hyper-phosphorylated Tau, and TAR DNA-binding protein 43 (TDP-43), are some of the most frequently reported proteins upregulated following a TBI and are also closely linked to PD. Recently, upregulation of Leucine Rich Repeat Kinase 2 (LRRK2), has been found in the brain of mice following a TBI. Subset of Rab proteins were identified as biological substrates of LRRK2, a protein also extensively linked to late onset PD. Inhibition of LRRK2 was found to be neuroprotective in PD and TBI models. The goal of this review is to survey current literature concerning the mechanistic overlap between TBI and PD with a particular focus on inflammation, metabolic dysregulation, and aforementioned proteins. This review will also cover the application of rodent TBI models to further our understanding of the relationship between TBI and PD.

Effect of mild blast-induced TBI on dendritic architecture of the cortex and hippocampus in the mouse.

Traumatic brain injury (TBI) has been designated as a signature injury of modern military conflicts. Blast trauma, in particular, has come to make up a significant portion of the TBIs which are sustained in warzones. Though most TBIs are mild, even mild TBI can induce long term effects, including cognitive and memory deficits. In our study, we utilized a mouse model of mild blast-related TBI (bTBI) to investigate TBI-induced changes within the cortex and hippocampus. We performed rapid Golgi staining on the layer IV and V pyramidal neurons of the parietal cortex and the CA1 basilar tree of the hippocampus and quantified dendritic branching and distribution. We found decreased dendritic branching within both the cortex and hippocampus in injured mice. Within parietal cortex, this decreased branching was most evident within the middle region, while outer and inner regions resembled that of control mice. This study provides important knowledge in the study of how the shockwave associated with a blast explosion impacts different brain regions.

Behavior, protein, and dendritic changes after model traumatic brain injury and treatment with nanocoffee particles.

BACKGROUND: Traumatic brain injury (TBI) is a widespread public health problem and a signature injury of our military in modern conflicts. Despite the long-term effects of even mild brain injuries, an effective treatment remains elusive. Coffee and several of its compounds, including caffeine, have been identified as having neuroprotective effects in studies of neurodegenerative disease. Given the molecular similarities between TBI and neurodegenerative disease, we have devised a study to test a nanocoffee extract in the treatment of a mouse model of mild TBI. RESULTS: After a single injury and two subsequent injections of nanocoffee, we identified treatment as being associated with improved behavioral outcomes, favorable molecular signaling changes, and dendritic changes suggestive of improved neuronal health. CONCLUSIONS: We have identified coffee extracts as a potential viable multifaceted treatment approach to target the secondary injury associated with TBI.

Thrombin and the Coag-Inflammatory Nexus in Neurotrauma, ALS, and Other Neurodegenerative Disorders.

This review details our current understanding of thrombin signaling in neurodegeneration, with a focus on amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease) as well as future directions to be pursued. The key factors are multifunctional and involved in regulatory pathways, namely innate immune and the coagulation cascade activation, that are essential for normal nervous system function and health. These two major host defense systems have a long history in evolution and include elements and regulators of the coagulation pathway that have significant impacts on both the peripheral and central nervous system in health and disease. The clotting cascade responds to a variety of insults to the CNS including injury and infection. The blood brain barrier is affected by these responses and its compromise also contributes to these detrimental effects. Important molecules in signaling that contribute to or protect against neurodegeneration include thrombin, thrombomodulin (TM), protease activated receptor 1 (PAR1), damage associated molecular patterns (DAMPs), such as high mobility group box protein 1 (HMGB1) and those released from mitochondria (mtDAMPs). Each of these molecules are entangled in choices dependent upon specific signaling pathways in play. For example, the particular cleavage of PAR1 by thrombin vs. activated protein C (APC) will have downstream effects through coupled factors to result in toxicity or neuroprotection. Furthermore, numerous interactions influence these choices such as the interplay between HMGB1, thrombin, and TM. Our hope is that improved understanding of the ways that components of the coagulation cascade affect innate immune inflammatory responses and influence the course of neurodegeneration, especially after injury, will lead to effective therapeutic approaches for ALS, traumatic brain injury, and other neurodegenerative disorders.

Mild blast-related TBI in a mouse model alters amygdalar neurostructure and circuitry.

Traumatic brain injury (TBI) continues to be a signature injury of our modern conflicts. Due in part to increased use of improvised explosive devices (IEDs), we have seen blast trauma make up a significant portion of TBIs sustained by deployed troops and civilians. In addition to the physical injury, TBI is also a common comorbidity with post-traumatic stress disorder (PTSD). Previous research suggests that PTSD is often associated with increased signaling within the amygdala, leading to feelings of fear and hyperarousal. In our study, we utilized a mouse model of mild blast-related TBI (bTBI) to investigate how TBI induces changes within the amygdala, which may provide favorable conditions for the development of PTSD. To do this, we performed Golgi staining on the stellate neurons of the basolateral amygdala and quantified dendritic amount, distribution, and complexity. We found increases in dendritic branching and in the density of dendritic spines in injured mice. Increases in spine density appears to be primarily due to increases in memory associated mushroom type dendritic spines. These changes observed in our bTBI model that are consistent with chronic stress models, suggesting an important connection between the physical changes induced by TBI and the neurological symptoms of PTSD.

Neuromuscular Junction Morphology and Gene Dysregulation in the Wobbler Model of Spinal Neurodegeneration.

Amyotrophic lateral sclerosis (ALS) is the most common adult-onset neuromuscular disease for which there is currently no effective treatment. The progression of ALS includes loss of motor neurons controlling the voluntary muscles, with much of this loss occurring at the neuromuscular junction. In an effort to better understand changes at the neuromuscular junction, we utilized the wobbler mouse model of motor neuron loss. We examined biceps and end plate morphologies and monitored selected factors involved in end plate function. Structural volumes were determined from 3D reconstructions that were generated for the end plates. Wobbler mice exhibited size reductions of both the muscle fibers and the end plates within the biceps, and we found that the end plate volumes were the most sensitive indicator of the degeneration. Concurrently, we found increases in calcitonin gene-related peptide (CGRP) and its receptor in wobbler biceps and spinal cord. We also found increases in gene expression of two acetylcholine receptors within the wobbler biceps, which may be a result of altered CGRP/CALCRL (calcitonin receptor-like receptor) expression.