Traumatic Brain Injury Animals Research Articles

Positive allosteric modulation of the α7 nicotinic acetylcholine receptor as a treatment for cognitive deficits after traumatic brain injury.

Cognitive impairments are a common consequence of traumatic brain injury (TBI). The hippocampus is a subcortical structure that plays a key role in the formation of declarative memories and is highly vulnerable to TBI. The α7 nicotinic acetylcholine receptor (nAChR) is highly expressed in the hippocampus and reduced expression and function of this receptor are linked with cognitive impairments in Alzheimer's disease and schizophrenia. Positive allosteric modulation of α7 nAChRs with AVL-3288 enhances receptor currents and improves cognitive functioning in naïve animals and healthy human subjects. Therefore, we hypothesized that targeting the α7 nAChR with the positive allosteric modulator AVL-3288 would enhance cognitive functioning in the chronic recovery period of TBI. To test this hypothesis, adult male Sprague Dawley rats received moderate parasagittal fluid-percussion brain injury or sham surgery. At 3 months after recovery, animals were treated with vehicle or AVL-3288 at 30 min prior to cue and contextual fear conditioning and the water maze task. Treatment of TBI animals with AVL-3288 rescued learning and memory deficits in water maze retention and working memory. AVL-3288 treatment also improved cue and contextual fear memory when tested at 24 hr and 1 month after training, when TBI animals were treated acutely just during fear conditioning at 3 months post-TBI. Hippocampal atrophy but not cortical atrophy was reduced with AVL-3288 treatment in the chronic recovery phase of TBI. AVL-3288 application to acute hippocampal slices from animals at 3 months after TBI rescued basal synaptic transmission deficits and long-term potentiation (LTP) in area CA1. Our results demonstrate that AVL-3288 improves hippocampal synaptic plasticity, and learning and memory performance after TBI in the chronic recovery period. Enhancing cholinergic transmission through positive allosteric modulation of the α7 nAChR may be a novel therapeutic to improve cognition after TBI.

When Two Wrongs Make a Right: The Effect of Acute and Chronic Binge Drinking on Traumatic Brain Injury Outcomes in Young Adult Female Rats.

Alcohol is the most commonly abused drug by young adults across North America. Although alcohol consumption itself incurs a risk of neurological damage, it is also a significant risk factor for traumatic brain injury (TBI). TBI among young adults is described as a modern healthcare epidemic. The drastic changes occurring within their neurological networks put young adults at greater risk for developing long-term post-traumatic deficits. Contradictory findings have been indicated regarding the effects of alcohol consumption on TBI outcomes in adults, with some studies demonstrating detrimental effects, whereas others suggest neuroprotective abilities. However, little is known about the effects of alcohol consumption on TBI outcomes during the sensitive stage of early adulthood. Young adult female Sprague-Dawley rats were randomly assigned to one of six experimental conditions: Pre-injury alcohol+TBI; Pre-injury alcohol+Sham; Pre- and Post-injury alcohol+TBI; Pre- and Post-injury alcohol+Sham; No alcohol+TBI; No alcohol+Sham. Alcohol consumption groups received an amount of 10% v/v ethanol solution based on the animals' weight. Following the injury, the rats were subjected to a behavioral test battery to assess post-concussive symptomology. Overall, chronic binge drinking significantly improved TBI outcomes related to motor coordination and balance, whereas binge drinking in general significantly decreased anxiety-like behaviors. Additionally, in many cases, chronic binge drinking appears to return the TBI animal's behavioral outcomes to levels comparable to those of the no alcohol sham animals. Thus, the results suggest that alcohol may exhibit neuroprotective abilities in the context of early adulthood TBI.

The role of NLRP3 in traumatic brain injury and its regulation by pioglitazone.

Perilesional edema is a predominant mechanism underlying secondary brain injury after traumatic brain injury (TBI). Perilesional edema is characterized by inflammation, production of proinflammatory cytokines, and migration of peripheral immune cells into the brain. The nucleotide-binding domain and leucine-rich repeat (NLR) family pyrin domain-containing 3 protein (NLRP3) is a key component of secondary injury. Pioglitazone regulates NLRP3 and other inflammatory cytokines. In the present study, the role of NLRP3 and the pharmacological effects of pioglitazone were investigated in animal TBI models. Brain contusion was induced in a weight drop model involving 3 groups of mice: C57 BL/6 (sham group), NLRP3 knockout (K/O group), and pioglitazone-treated mice (treatment group). The percentage of brain water content of the 3 groups of mice was compared over a period of time. Western blot, immunohistochemistry, and immunofluorescence analyses were conducted to investigate NLRP3-related inflammasomes and the effects of pioglitazone in the TBI models. Brain edema was the highest on day 3 after TBI in the sham group. Brain edema in both the K/O and the treatment groups was lower than in the sham group. In Western blot, the expression of inflammasomes was higher after TBI in the sham group, but the expression of interleukin-1β, caspase-1, and NLRP3 was decreased significantly following treatment with pioglitazone. The expression of GFAP (glial fibrillary acidic protein) and Iba1 was decreased in both the K/O and treatment groups. In addition, confocal microscopy revealed a decrease in microglial cell and astrocyte activation following pioglitazone therapy. The inflammasome NLRP3 plays a pivotal role in regulating cerebral edema and secondary inflammation. Interestingly, pioglitazone reduced cerebral edema and immune response after TBI by downregulating the effects of NLRP3. These results suggest that the clinical application of pioglitazone may be a neuroprotective strategy in TBI.

Abstracts from The 37th Annual National Neurotrauma Symposium June 29–July 3, 2019 Pittsburgh, Pennsylvania

Abstracts from The 37^th Annual National Neurotrauma Symposium June 29–July 3, 2019 Pittsburgh, Pennsylvania

PLA2G4A/cPLA2-mediated lysosomal membrane damage leads to inhibition of autophagy and neurodegeneration after brain trauma

ABSTRACT Lysosomal membrane permeabilization (LMP) is observed under many pathological conditions, leading to cellular dysfunction and death. However, the mechanisms by which lysosomal membranes become leaky in vivo are not clear. Our data demonstrate that LMP occurs in neurons following controlled cortical impact induced (CCI) traumatic brain injury (TBI) in mice, leading to impaired macroautophagy (autophagy) and neuronal cell death. Comparison of LC-MS/MS lysosomal membrane lipid profiles from TBI and sham animals suggested a role for PLA2G4A/cPLA2 (phospholipase A2, group IVA [cytosolic, calcium-dependent]) in TBI-induced LMP. Activation of PLA2G4A caused LMP and inhibition of autophagy flux in cell lines and primary neurons. In vivo pharmacological inhibition of PLA2G4A attenuated TBI-induced LMP, as well as subsequent impairment of autophagy and neuronal loss, and was associated with improved neurological outcomes. Inhibition of PLA2G4A in vitro limited amyloid-β-induced LMP and inhibition of autophagy. Together, our data indicate that PLA2G4A -mediated lysosomal membrane damage is involved in neuronal cell death following CCI-induced TBI and potentially in other neurodegenerative disorders. Abbreviations AACOCF3, arachidonyl trifluoromethyl ketone; ACTB/β-actin, actin, beta; AD, Alzheimer disease; ATG5, autophagy related 5; ATG7, autophagy related 7; ATG12, autophagy related 12; BECN1, beclin 1, autophagy related; C1P, ceramide-1-phosphate; CCI, controlled cortical impact; CTSD, cathepsin D; CTSL, cathepsin L; GFP, green fluorescent protein; IF, immunofluorescence; LAMP1, lysosomal-associated membrane protein 1; LAMP2, lysosomal-associated membrane protein 2; LC-MS/MS, liquid chromatography-tandem mass spectrometry; LMP, Lysosomal membrane permeabilization; LPC, lysophosphatidylcholine; LPE, lysophosphatidylethanolamine; MAP1LC3/LC3, microtuble-associated protein 1 light chain 3; NAGLU, alpha-N-acetylglucosaminidase (Sanfilippo disease IIIB); PC, diacyl glycerophosphatidylcholine; PE, diacyl glycerophosphatidylethanolamine; PE-O, plasmanyl glycerophosphatidylethanolamine; PE-P, plasmenyl glycerophosphatidylethanolamine; PLA2G4A/cPLA2, phospholipase A2, group IVA (cytosolic, calcium-dependent); RBFOX3, RNA binding protein, fox-1 homolog (C. elegans) 3; RFP, red fluorescent protein; ROS, reactive oxygen species; SQSTM1, sequestosome 1; TUBA1/α-tubulin, tubulin, alpha; TBI, traumatic brain injury; TFEB, transcription factor EB; ULK1, unc-51 like kinase 1.

Potential therapeutic role of melatonin in traumatic brain injury: A literature review

Oxidative stress induces excessive production of reactive oxygen species (ROS). ROS are including several free oxygen radicals such as singlet oxygen and superoxide radical. Excessive ROS production induces injuries of lipids, nucleic acids and proteins in several cells. Brain and neurons have a high amount of polyunsaturated fatty acids (PUFAs) and consumption of oxygen, but they have low level of antioxidant. Oxidative stress is controlled by several enzymatic and non-enzymatic antioxidants. One of the main nonenzymatic antioxidant is melatonin. Melatonin is secreted from the pineal gland by physiological circadian cycles. It has several physiological functions such as mediator of circannual reproductive rhythms (Tamtaji et al. 2019). However, it has also a regulatory role in the pathophysiological pathways of traumatic brain injury (TBI) in human and rodents (Barlow et al. 2019). TBI is one of the most common causes of the mortalities. Secondary events occur after primary events like shearing of nerve cells and blood vessels, cause posttraumatic neurodegenerations with an increase in ROS and ROS-mediated lipid peroxidation. It was reported that TBI-induced oxidative stress in experimental TBI was inhibited by the melatonin treatment (Senol and Nazıroğlu, 2014). Results of a recent study indicated protective role of melatonin through inhibition of Nrf2 signaling pathway, inflammation and oxidative stress in TBI-induced mice (Wang et al. 2019). In human studies, behavioral outcomes of TBI were modulated by the melatonin treatment (Barlow et al. 2019). In the oral presentation, I will review recent studies on TBI in human and experimental animals.   In conclusion, there are pre-clinical and clinical evidences that melatonin treatment after TBI significantly improves both behavior-cognition outcomes and pathophysiological outcomes such as oxidative stress and inflammation. It seems that the certain interaction between melatonin and TBI still remain to be determined.

Pioglitazone ameliorates neuronal damage after traumatic brain injury via the PPARγ/NF-κB/IL-6 signaling pathway

Traumatic brain injury (TBI) is the major cause of high mortality and disability rates worldwide. Pioglitazone is an activator of peroxisome proliferator-activated receptor-gamma (PPARγ) that can reduce inflammation following TBI. Clinically, neuroinflammation after TBI lacks effective treatment. Although there are many studies on PPARγ in TBI animals, only few could be converted into clinical, since TBI mechanisms in humans and animals are not completely consistent. The present study, provided a potential theoretical basis and therapeutic target for neuroinflammation treatment after TBI. First, we detected interleukin-6 (IL-6), nitric oxide (NO) and Caspase-3 in TBI clinical specimens, confirming a presence of a high expression of inflammatory factors. Western blot (WB), quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC) were used to detect PPARγ, IL-6, and p-NF-κB to identify the mechanisms of neuroinflammation. Then, in the rat TBI model, neurobehavioral and cerebral edema levels were investigated after intervention with pioglitazone (PPARγ activator) or T0070907 (PPARγ inhibitor), and PPARγ, IL-6 and p-NF-κB were detected again by qRT-PCR, WB and immunofluorescence (IF). The obtained results revealed that: 1) increased expression of IL-6, NO and Caspase-3 in serum and cerebrospinal fluid in patients after TBI, and decreased PPARγ in brain tissue; 2) pioglitazone could improve neurobehavioral and reduce brain edema in rats after TBI; 3) the protective effect of pioglitazone was achieved by activating PPARγ and reducing NF-κB and IL-6. The neuroprotective effect of pioglitazone on TBI was mediated through the PPARγ/NF-κB/IL-6 pathway.

Brain Trauma Disrupts Hepatic Lipid Metabolism: Blame It on Fructose?

The action of brain disorders on peripheral metabolism is poorly understood. The impact of traumatic brain injury (TBI) on peripheral organ function and how TBI effects can be influenced by the metabolic perturbation elicited by fructose ingestion are studied. It is found that TBI affects glucose metabolism and signaling proteins for insulin and growth hormone in the liver; these effects are exacerbated by fructose ingestion. Fructose, principally metabolized in the liver, potentiates the action of TBI on hepatic lipid droplet accumulation. Studies in isolated cultured hepatocytes identify GH and fructose as factors for the synthesis of lipids. The liver has a major role in the synthesis of lipids used for brain function and repair. TBI results in differentially expressed genes in the hypothalamus, primarily associated with lipid metabolism, providing cues to understand central control of peripheral alterations. Fructose-fed TBI animals have elevated levels of markers of inflammation, lipid peroxidation, and cell energy metabolism, suggesting the pro-inflammatory impact of TBI and fructose in the liver. Results reveal the impact of TBI on systemic metabolism and the aggravating action of fructose. The hypothalamic-pituitary-growth axis seems to play a major role in the regulation of the peripheral TBI pathology.

Chronic synaptic insulin resistance after traumatic brain injury abolishes insulin protection from amyloid beta and tau oligomer-induced synaptic dysfunction

Traumatic brain injury (TBI) is a risk factor for Alzheimer’s disease (AD), although the mechanisms contributing to this increased risk are unknown. Insulin resistance is an additional risk factor for AD whereby decreased insulin signaling increases synaptic sensitivity to amyloid beta (Aβ) and tau. Considering this, we used rats that underwent a lateral fluid percussion injury at acute and chronic time-points to investigate whether decreased insulin responsiveness in TBI animals is playing a role in synaptic vulnerability to AD pathology. We detected acute and chronic decreases in insulin responsiveness in isolated hippocampal synaptosomes after TBI. In addition to assessing both Aβ and tau binding on synaptosomes, we performed electrophysiology to assess the dysfunctional impact of Aβ and tau oligomers as well as the protective effect of insulin. While we saw no difference in binding or degree of LTP inhibition by either Aβ or tau oligomers between sham and TBI animals, we found that insulin treatment was able to block oligomer-induced LTP inhibition in sham but not in TBI animals. Since insulin treatment has been discussed as a therapy for AD, this gives valuable insight into therapeutic implications of treating AD patients based on one’s history of associated risk factors.

Modeling sports-related mild traumatic brain injury in animals-A systematic review.

Sports-related head trauma has emerged as an important public health issue, as mild traumatic brain injuries (mTBIs) may result in neurodegenerative disorders such as chronic traumatic encephalopathy (CTE). Research into mTBI and CTE pathophysiology are difficult to undertake in athletes, with observational trials and post-mortem analysis the current mainstays. Thus, animal models play an important role in the study of mTBI, however, traditional animal models have focused on acute, severe injuries rather than the more typical mTBI's seen in sport injuries. Recently, anumber of animal models have been developed that are both appropriately scaled and biomechanically relevant to the forces sustained by athletes. This review aimed to examine the literature for variables included in these animal models, and the resulting neurotrauma as evidenced by pathology and behavioral deficits. A systematic search of the literature was performed in multiple electronic databases. The inclusion criteria required mimicry of athlete mTBI conditions: freedom of head movement, lack of surgical alteration of the skull, and application of direct contact force. Studies were analyzed for variables including apparatus design features (impact force, change in animal head velocity, and kinetic energy transfer to the head), demonstrated pathology (phosphorylated tau, TDP-43 aggregation, diffuse axonal injury, gliosis, cytokine inflammation response, and genetic integrity), and behavioral changes. These studies suggested that appropriate animal models can assist in understanding the pathological and functional outcomes of athlete mTBI, and could be used as a platform for future studies of diagnostic/prognostic markers and in the development of treatment interventions.

Clinical Relevance of Behavior Testing in Animal Models of Traumatic Brain Injury.

Traumatic brain injury (TBI) is a leading cause of morbidity worldwide, with patients often suffering from consequences such as cognitive deficits, social abnormalities, anxiety, depression, pain, and motor dysfunction. Given that these impairments often have a significant impact on the patient's quality of life, a key aim of therapeutic intervention in TBI is to mitigate these effects. Translational strategies to develop such interventions have heavily featured animal models of TBI. To assess the efficacy of interventions in these models, a range of behavioral outcomes are utilized. However, in light of the past translational failures that have plagued the TBI field, the clinical relevance of these preclinical behavioral tests is now being scrutinized. This article will summarize the behavioral consequences of TBI in humans; describe common methods available for testing cognition, social function, motor ability, pain, as well as depression- and anxiety-like behaviors in animal models of TBI; provide an overview of the results from TBI animal model studies that have utilized these methods; and discuss these pre-clinical behavior methods and findings in terms of their relevance to the clinical TBI setting. We conclude that there is translational value in these methods and their related findings, but also suggest strategies and future research to improve the clinical relevance of behavior testing in animal models of TBI.

Frequency-Dependent Changes in Resting State Electroencephalogram Functional Networks after Traumatic Brain Injury in Piglets.

Traumatic brain injury (TBI) is a major health concern in children, as it can cause chronic cognitive and behavioral deficits. The lack of objective involuntary metrics for the diagnosis of TBI makes prognosis more challenging, especially in the pediatric context, in which children are often unable to articulate their symptoms. Resting state electroencephalograms (EEG), which are inexpensive and non-invasive, and do not require subjects to perform cognitive tasks, have not yet been used to create functional brain networks in relation to TBI in children or non-human animals; here we report the first such study. We recorded resting state EEG in awake piglets before and after TBI, from which we generated EEG functional networks from the alpha (8-12 Hz), beta (16.5-25 Hz), broad (1-35 Hz), delta (1-3.5 Hz), gamma (30-35 Hz), sigma (13-16 Hz), and theta (4-7.5 Hz) frequency bands. We hypothesize that mild TBI will induce persistent frequency-dependent changes in the 4-week-old piglet at acute and chronic time points. Hyperconnectivity was found in several frequency band networks after TBI. This study serves as proof of concept that the study of EEG functional networks in awake piglets may be useful for the development of diagnostic metrics for TBI in children.

Diffusion MR imaging acquisition and analytics for microstructural delineation in pre-clinical models of TBI.

Significant progress has been made toward improving both the acquisition of clinical diffusion-weighted imaging (DWI) data and its analysis in the uninjured brain, through various techniques including a large number of model-based solutions that have been proposed to fit for multiple tissue compartments, and multiple fibers per voxel. While some of these techniques have been applied to clinical traumatic brain injury (TBI) research, the majority of these technological enhancements have yet to be fully implemented in the preclinical arena of TBI animal model-based research. In this review, we describe the requirement for preclinical, MRI-based efforts to provide systematic confirmation of the applicability of some of these models as indicators of tissue pathology within the injured brain. We review how current DWI techniques are currently being used in animal TBI models, and describe how both acquisition and analytic techniques could be extended to leverage the progress made in clinical work. Finally, we highlight remaining gaps in the preclinical pipeline from data acquisition to final analysis that currently have no real, preclinical-based correlate.

Traumatic brain injury and resultant pituitary dysfunction: insights from experimental animal models.

Traumatic brain injury (TBI) is a major worldwide cause of disability, often burdening young people with serious lifelong health problems. A frequent clinical complication is post-traumatic hypopituitarism (PTHP) manifesting in several hypothalamus-pituitary axes. The head trauma-induced mechanisms underlying PTHP remain largely unknown. Several hypotheses have been proposed including direct damage to the pituitary gland and hypothalamus, vascular events and autoimmunity. This review aims to provide a summary of the currently limited number of studies exploring hypothalamus-pituitary dysfunction in experimental animal TBI models. Although the impact of different forms of TBI on a number of hypothalamus-pituitary axes has been investigated, consequences for pituitary tissue and function have only scarcely been described. Moreover, mechanisms underlying the endocrine dysfunctions remain under explored. Studies on TBI-induced pituitary dysfunction are still scarce. More research is needed to acquire mechanistic insights into the pathophysiology of PTHP which may eventually open up the horizon toward better treatments, including pituitary-regenerative approaches.

Studies on long term behavioural changes in group-housed rat models of brain and spinal cord injury using an automated home cage recording system

BackgroundNeurotrauma patients face major neurological sequelae. The failure in the preclinical-to-clinical translation of candidate therapies could be due to poor evaluation of rodent behaviours after neurotrauma. New MethodA home cage automated system was used to study the long term behaviour of individual rats with traumatic brain injury (TBI), spinal cord injury (SCI) and non-CNS injured controls, whilst group-housed in their home cages. Naïve rats were used as baseline controls. Automated locomotor activity and body temperature recordings were carried out 24 h /day for 3 days/week during 12 weeks post-injury. Behavioural patterns, including aggression, rearing, grooming, feeding and drinking were analysed from automated video recordings during week 1, 6 and 12. ResultsSCI animals showed a lower locomotor activity compared to TBI or control animals during light and dark phases. TBI animals showed a higher aggression during the dark phase in the first week post-injury compared to SCI or control animals. Individual grooming and rearing were reduced in SCI animals compared to TBI and control animals in the first week post-injury during the dark phase. No differences in drinking or feeding were detected between groups. Locomotor activity did not differ between naïve male and female rats, but body temperature differ between light and dark phases for both. Standard methodsInjury severity was compared to standard SCI and TBI behaviour scores (BBB and mNSS, respectively) and histological analysis. ConclusionsThis study demonstrates the practical benefits of using a non-intrusive automated home cage recording system to observe long term individual behaviour of group-housed SCI and TBI rats.

Cognitive and neuropsychiatric impairments vary as a function of injury severity at 12 months post-experimental diffuse traumatic brain injury: Implications for dementia development.

Traumatic brain injury (TBI) is a common risk factor for later neurodegeneration, which can manifest as dementia. Despite this, little is known about the time-course of development of functional deficits, particularly cognitive and neuropsychiatric impairments, and whether these differ depending on the nature of the initiating insult. Therefore, this study investigated long term functional impairment at 12 months post-injury following diffuse TBI of different severities. Male Sprague-Dawley rats (420-480 g; 10-12 weeks) were either given a sham surgery (n = 14) or subjected to Marmarou's impact acceleration model of diffuse TBI for a single mild TBI (n = 12), repetitive mild TBI (3 mild diffuse injuries at 5 day intervals) (n = 14) or moderate to severe TBI (n = 14). At 12 months after injury, they were tested on a functional battery encompassing motor, neuropsychiatric (anxiety and depressive-like) and cognitive function. Our results showed that moderate to severe TBI animals exhibited significant impairments in cognitive flexibility (p = 0.009) on the Barnes maze when compared to age-matched sham animals. Neither repetitive mild TBI nor single mild TBI animals showed significant functional impairments when compared to shams. Thus, this study provides the first insight into chronic functional impairments associated with different severities of diffuse TBI, with moderate to severe TBI being a higher risk factor for impaired cognitive function at 12 months post-injury. Taken together, this may have implications for risk of dementia development following different severities of injury.

The Importance of Therapeutic Time Window in the Treatment of Traumatic Brain Injury.

Traumatic brain injury (TBI) is a major cause of death and disability. Despite its importance in public health, there are presently no drugs to treat TBI. Many reasons underlie why drugs have failed clinical trials, one reason is that most drugs to treat TBI lose much of their efficacy before patients are first treated. This review discusses the importance of therapeutic time window; the time interval between TBI onset and the initiation of treatment. Therapeutic time window is complex, as brain injury is both acute and chronic, resulting in multiple drug targets that appear and disappear with differing kinetics. The speed and increasing complexity of TBI pathophysiology is a major reason why drugs lose efficacy as time to first dose increases. Recent Phase III clinical trials treated moderate to severe TBI patients within 4–8 h after injury, yet they turned away many potential patients who could not be treated within these time windows. Additionally, most head trauma is mild TBI. Unlike moderate to severe TBI, patients with mild TBI often delay treatment until their symptoms do not abate. Thus, drugs to treat moderate to severe TBI likely will need to retain high efficacy for up to 12 h after injury; drugs for mild TBI, however, will likely need even longer windows. Early pathological events following TBI progress with similar kinetics in humans and animal TBI models suggesting that preclinical testing of time windows assists the design of clinical trials. We reviewed preclinical studies of drugs first dosed later than 4 h after injury. This review showed that therapeutic time window can differ depending upon the animal TBI model and the outcome measure. We identify the few drugs (methamphetamine, melanocortin, minocycline plus N-acetylcysteine, and cycloserine) that demonstrated good therapeutic windows with multiple outcome measures. On the basis of their therapeutic window, these drugs appear to be excellent candidates for clinical trials. In addition to further testing of these drugs, we recommend that the assessment of therapeutic time window with multiple outcome measures becomes a standard component of preclinical drug testing.

Neuroimaging of Subacute Brain Inflammation and Microstructural Changes Predicts Long-Term Functional Outcome after Experimental Traumatic Brain Injury.

There is currently a lack of prognostic biomarkers to predict the different sequelae following traumatic brain injury (TBI). The present study investigated the hypothesis that subacute neuroinflammation and microstructural changes correlate with chronic TBI deficits. Rats were subjected to controlled cortical impact (CCI) injury, sham surgery, or skin incision (naïve). CCI-injured (n = 18) and sham-operated rats (n = 6) underwent positron emission tomography (PET) imaging with the translocator protein 18 kDa (TSPO) radioligand [18F]PBR111 and diffusion tensor imaging (DTI) in the subacute phase (≤3 weeks post-injury) to quantify inflammation and microstructural alterations. CCI-injured, sham-operated, and naïve rats (n = 8) underwent behavioral testing in the chronic phase (5.5-10 months post-injury): open field and sucrose preference tests, two one-week video-electroencephalogram (vEEG) monitoring periods, pentylenetetrazole (PTZ) seizure susceptibility tests, and a Morris water maze (MWM) test. In vivo imaging revealed pronounced neuroinflammation, decreased fractional anisotropy, and increased diffusivity in perilesional cortex and ipsilesional hippocampus of CCI-injured rats. Behavioral analysis revealed disinhibition, anhedonia, increased seizure susceptibility, and impaired learning in CCI-injured rats. Subacute TSPO expression and changes in DTI metrics significantly correlated with several chronic deficits (Pearson's |r| = 0.50-0.90). Certain specific PET and DTI parameters had good sensitivity and specificity (area under the receiver operator characteristic [ROC] curve = 0.85-1.00) to distinguish between TBI animals with and without particular behavioral deficits. Depending on the investigated behavioral deficit, PET or DTI data alone, or the combination, could very well predict the variability in functional outcome data (adjusted R2 = 0.54-1.00). Taken together, both TSPO PET and DTI seem promising prognostic biomarkers to predict different chronic TBI sequelae.

Frontal brain injury chronically impairs timing behavior in rats

Traumatic brain injury (TBI) affects over 2.8 million people annually, and has been shown to increase motor impulsivity in both humans and animals. However, the root cause of this behavioral disinhibition is not fully understood. The goal of the current study was to evaluate whether timing behavior is disrupted after TBI, which could potentially explain increases in impulsive responding. Twenty-one male three-month old Long-Evans rats were trained on a fixed interval-18 s schedule. Following training, rats were placed on the Peak Interval Procedure, with intermittent peak trials. On peak trials, no behaviors were reinforced and response rates were recorded to determine timing ability. After reaching a stable baseline, rats received bilateral frontal TBI (n = 12) using controlled cortical impact or sham procedures (n = 9). After one week recovery, rats were re-assessed on the Peak Procedure for six weeks. An amphetamine challenge was carried out after behavior reached stable post-injury performance. TBI caused a chronic decrease/acceleration in peak time, increase in response variability, and reduction in response rate. The shifted peak time suggests that altered perception of time may contribute to impairments in response inhibition after TBI. Amphetamine significantly increased response variability, with TBI animals demonstrating greater sensitivity, but did not affect peak time in either group. These data suggest that timing may not be the sole factor explaining impulsive action after TBI given that amphetamine reduced motor impulsivity in prior studies. Further investigations will be needed to dissociate the effects of amphetamine on TBI with regard to timing behavior.

Enhancement of Brain d-Serine Mediates Recovery of Cognitive Function after Traumatic Brain Injury.

Cognitive deficits, especially memory loss, are common and devastating neuropsychiatric sequelae of traumatic brain injury (TBI). The deficits may persist for years and may be accompanied by increased risk of developing early- onset dementia. Past attempts to reverse the neuropathological effects of brain injury with glutamate-N-methyl-d-aspartate (NMDA) antagonists failed to show any benefits or worsened the outcome, suggesting that activation, rather than blockage, of the NMDA receptor (NMDAR) may be useful in the subacute period after TBI and stroke. Activation of the NMDAR requires occupation of the glycine-modulatory site by co-agonists to achieve its synaptic functions. Glycine and d-serine are endogenous ligands/co-agonists of synaptic NMDARs in many areas of the mature brain. The aim of the present study was to evaluate the effect of 6-chlorobenzo(d)isoxazol-3-ol (CBIO), an inhibitor of D-amino acid oxidase (DAAO), which degrades d-serine, on cognitive outcome in a mouse model of TBI. Because treating TBI animals with CBIO elevates the endogenous levels of d-serine, we compared this novel treatment with treatment by exogenous d-serine alone and combined with CBIO. The results show that a single treatment (24 h post-injury) with CBIO in the mouse model of closed head injury significantly improves cognitive and motor function, and decreases lesion volume and the inflammatory response. Moreover, the compound proved to be neuroprotective, as the hippocampal volume and the number of neurons in hippocampal regions increased. Treatment with CBIO boosted the NR1 and phospho- NR1 subunits of the NMDAR and affected the CREB, phospho-CREB, and brain-derived neurotropic factor (BDNF) pathways. These findings render CBIO a promising, novel treatment for cognitive impairment following TBI.