Acute gut microbiome changes after traumatic brain injury are associated with chronic deficits in decision-making and impulsivity in male rats.

The mechanisms underlying chronic psychiatric-like impairments after traumatic brain injury (TBI) are currently unknown. The goal of the present study was to assess the role of diet and the gut microbiome in psychiatric symptoms after TBI. Rats were randomly assigned to receive a high-fat diet (HFD) or calorie-matched low-fat diet (LFD). After 2 weeks of free access, rats began training on the rodent gambling task (RGT), a measure of risky decision-making and motor impulsivity. After training, rats received a bilateral frontal TBI or a sham procedure and continued postinjury testing for 10 weeks. Fecal samples were collected before injury and 3-, 30-, and 60 days postinjury to evaluate the gut microbiome. HFD altered the microbiome, but ultimately had low-magnitude effects on behavior and did not modify functional outcomes after TBI. Injury-induced functional deficits were far more robust; TBI substantially decreased optimal choice and increased suboptimal choice and motor impulsivity on the RGT. TBI also affected the microbiome, and a model comparison approach revealed that bacterial diversity measured 3 days postinjury was predictive of chronic psychiatric-like deficits on the RGT. A functional metagenomic analysis identified changes to dopamine and serotonin synthesis pathways as a potential candidate mechanism. Thus, the gut may be a potential acute treatment target for psychiatric symptoms after TBI, as well as a biomarker for injury and deficit severity. However, further research will be needed to confirm and extend these findings. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Large-N Rat Data Enables Phenotyping of Risky Decision-Making: A Retrospective Analysis of Brain Injury on the Rodent Gambling Task.

Decision-making is substantially altered after brain injuries. Patients and rats with brain injury are more likely to make suboptimal, and sometimes risky choices. Such changes in decision-making may arise from alterations in how sensitive individuals are to outcomes. To assess this, we compiled and harmonized a large dataset from four studies of TBI, each of which evaluated behavior on the Rodent Gambling Task (RGT). We then determined whether the following were altered: (1) sensitivity to overall contingencies, (2) sensitivity to immediate outcomes, or (3) general choice phenotypes. Overall sensitivity was evaluated using the matching law, immediate sensitivity by looking at the probability of switching choices given a win or loss, and choice phenotypes by k-means clustering. We found significant reductions in sensitivity to the overall outcomes and a bias toward riskier alternatives in TBI rats. However, the substantial individual variability led to poor overall fits in matching analyses. We also found that TBI caused a significant reduction in the tendency to repeatedly choose a given option, but no difference in win- or loss-specific sensitivity. Finally, clustering revealed 5 distinct decision-making phenotypes and TBI reduced membership in the "optimal" type. The current findings support a hypothesis that TBI reduces sensitivity to contingencies. However, in the case of tasks such as the RGT, this is not a simple shift to indiscriminate or less discriminate responding. Rather, TBI rats are more likely to develop suboptimal preferences and frequently switch choices. Treatments will have to consider how this behavior might be corrected.

Effects of Cannabis-Delivered THC on mood and negative attentional bias in the context of positive vs. neutral Alternatives-a pilot study.

OBJECTIVE: To assess: (1) the acute effects of smoked marijuana (MJ) on negative attentional bias (NAB), (2) moderation of these effects by positive versus neutral alternatives, and (3) the associations of tetrahydrocannabinol (THC)-induced changes in NAB with changes in affect. METHODS: Fourteen MJ users (1-4 uses/wk) smoked a THC cigarette on 1 day and a placebo cigarette on the other counterbalanced day. After smoking, participants freely gazed back and forth at a series of two side-by-side pictures pairs presented for 3000 ms (one negative, while the other was either positive or neutral) while eye gaze was tracked. RESULTS: The effects of THC relative to placebo varied across time such that THC increased NAB during the early temporal component of threatening picture viewing, 333-858 ms after dual-picture onset, regardless of alternative picture valance. However, contrary to the attentional bias-causes affect hypothesis, during the early viewing phase THC-enhanced positive affect (PA) correlated positively with THC-induced NAB. In contrast, during the late phase (891-3000 ms) THC-enhanced PA did not correlate significantly with NAB, though THC-induced negative affect (NA) change did correlate positively with THC-induced change in NAB in the positive alternative condition. CONCLUSIONS: We replicated findings of others showing that THC can enhance NAB during the early stages of threatening picture viewing. We extended previous results by demonstrating the THC-induced NAB is associated with increased PA during initial threat viewing, but with increased NA during later processing if positive alternatives are present.

Repeat Closed-Head Injury in Male Rats Impairs Attention but Causes Heterogeneous Outcomes in Multiple Measures of Impulsivity and Glial Pathology.

Repetitive mild traumatic brain injury, or concussion, can lead to the development of long-term psychiatric impairments. However, modeling these deficits is challenging in animal models and necessitates sophisticated behavioral approaches. The current set of studies were designed to evaluate whether a rubberized versus metal impact tip would cause functional deficits, the number of injuries required to generate such deficits, and whether different psychiatric domains would be affected. Across two studies, male rats were trained in either the 5-choice serial reaction time task (5CSRT; Experiment 1) to assess attention and motor impulsivity or concurrently on the 5CSRT and the delay discounting task (Experiment 2) to also assess choice impulsivity. After behavior was stable, brain injuries were delivered with the Closed-head Injury Model of Engineered Rotational Acceleration (CHIMERA) either once per week or twice per week (Experiment 1) or just once per week (Experiment 2). Astrocyte and microglia pathology was also assayed in relevant regions of interest. CHIMERA injury caused attentional deficits across both experiments, but only increased motor impulsivity in Experiment 1. Surprisingly, choice impulsivity was actually reduced on the Delay Discounting Task after repeat injuries. However, subsequent analyses suggested potential visual issues which could alter interpretation of these and attentional data. Subtle changes in glial pathology immediately after the injury (Experiment 1) were attenuated after 4 weeks recovery (Experiment 2). Given the heterogenous findings between experiments, additional research is needed to determine the root causes of psychiatric disturbances which may arise as a results of repeated brain injuries.

Lateral Fluid Percussion Injury Causes Sex-Specific Deficits in Anterograde but Not Retrograde Memory.

Cognitive impairment is a common symptom after traumatic brain injury (TBI). Memory, in particular, is often disrupted during chronic post-injury recovery. To understand the sex-specific effects of brain injury on retrograde and anterograde memory, we examined paired associate learning (PAL), spatial learning and memory, and fear memory after lateral fluid percussion TBI. We hypothesized that male and female mice would display unique memory deficits after TBI. PAL task acquisition was initiated via touchscreen operant conditioning 22 weeks before sham injury or TBI. Post-injury PAL testing occurred 7 weeks post-injury. Barnes maze and fear conditioning were completed at 14- and 15-weeks post-injury, respectively. Contrary to our expectations, behavioral outcomes were not primarily influenced by TBI. Instead, sex-specific differences were observed in all tasks which exposed task-specific trends in male TBI mice. Male mice took longer to complete the PAL task, but this was not affected by TBI and did not compromise the ability to make a correct choice. Latency to reach the goal box decreased across testing days in Barnes maze, but male TBI mice lagged in improvement compared to all other groups. Use of two learning indices revealed that male TBI mice were deficient in transferring information from 1 day to the next. Finally, acquisition and contextual retention of fear memory were similar between all groups. Cued retention of the tone-shock pairing was influenced by both injury and sex. Male sham mice displayed the strongest cued retention of fear memory, evidenced by increased freezing behavior across the test trial. In contrast, male TBI mice displayed reduced freezing behavior with repetitive tone exposure. An inverse relationship in freezing behavior to tone exposure was detected between female sham and TBI mice, although the difference was not as striking. Together, these studies show that retrograde memory is intact after lateral TBI. However, male mice are more vulnerable to post-injury anterograde memory deficits. These behaviors were not associated with gross pathological change near the site injury or in subcortical brain regions associated with memory formation. Future studies that incorporate pre- and post-injury behavioral analysis will be integral in defining sex-specific memory impairment after TBI.

Cathodal Transcranial Direct-Current Stimulation Selectively Decreases Impulsivity after Traumatic Brain Injury in Rats.

Traumatic brain injury (TBI) often results in chronic psychiatric-like symptoms. In a condition with few therapeutic options, neuromodulation has emerged as a promising potential treatment avenue for these individuals. The goal of the current study was to determine if transcranial direct-current stimulation (tDCS) could treat deficits of impulsivity and attention in rats. This could then be used as a model to investigate treatment parameters and the mechanism of action underlying therapeutic effects. Rats were trained on a task to measure attention and motor impulsivity (five-choice serial reaction time task), then given a frontal, controlled cortical impact injury. After rats recovered to a new baseline, tDCS (cathodal, 10 min, 800 µA) was delivered daily prior to testing in a counterbalanced, cross-over design. Treatment with tDCS selectively reduced impulsivity in the TBI group, and the greatest recovery occurred in the rats with the largest deficits. With these data, we have established a rat model for studying the effects of tDCS on psychiatric-like dysfunction. More research is needed to determine the mechanism of action by which tDCS-related gains occur.

ApoA-I deficiency increases cortical amyloid deposition, cerebral amyloid angiopathy, cortical and hippocampal astrogliosis, and amyloid-associated astrocyte reactivity in APP/PS1 mice.

BACKGROUND: Alzheimer's disease (AD) is defined by amyloid beta (Aß) plaques and neurofibrillary tangles and characterized by neurodegeneration and memory loss. The majority of AD patients also have Aß deposition in cerebral vessels known as cerebral amyloid angiopathy (CAA), microhemorrhages, and vascular co-morbidities, suggesting that cerebrovascular dysfunction contributes to AD etiology. Promoting cerebrovascular resilience may therefore be a promising therapeutic or preventative strategy for AD. Plasma high-density lipoproteins (HDL) have several vasoprotective functions and are associated with reduced AD risk in some epidemiological studies and with reduced Aß deposition and Aß-induced inflammation in 3D engineered human cerebral vessels. In mice, deficiency of apoA-I, the primary protein component of HDL, increases CAA and cognitive dysfunction, whereas overexpression of apoA-I from its native promoter in liver and intestine has the opposite effect and lessens neuroinflammation. Similarly, acute peripheral administration of HDL reduces soluble Aß pools in the brain and some studies have observed reduced CAA as well. Here, we expand upon the known effects of plasma HDL in mouse models and in vitro 3D artery models to investigate the interaction of amyloid, astrocytes, and HDL on the cerebrovasculature in APP/PS1 mice. METHODS: APP/PS1 mice deficient or hemizygous for Apoa1 were aged to 12 months. Plasma lipids, amyloid plaque deposition, Aß protein levels, protein and mRNA markers of neuroinflammation, and astrogliosis were assessed using ELISA, qRT-PCR, and immunofluorescence. Contextual and cued fear conditioning were used to assess behavior. RESULTS: In APP/PS1 mice, complete apoA-I deficiency increased total and vascular Aß deposition in the cortex but not the hippocampus compared to APP/PS1 littermate controls hemizygous for apoA-I. Markers of both general and vascular neuroinflammation, including Il1b mRNA, ICAM-1 protein, PDGFRß protein, and GFAP protein, were elevated in apoA-I-deficient APP/PS1 mice. Additionally, apoA-I-deficient APP/PS1 mice had elevated levels of vascular-associated ICAM-1 in the cortex and hippocampus and vascular-associated GFAP in the cortex. A striking observation was that astrocytes associated with cerebral vessels laden with Aß or associated with Aß plaques showed increased reactivity in APP/PS1 mice lacking apoA-I. No behavioral changes were observed. CONCLUSIONS: ApoA-I-containing HDL can reduce amyloid pathology and astrocyte reactivity to parenchymal and vascular amyloid in APP/PS1 mice.

Repetitive closed-head impact model of engineered rotational acceleration (CHIMERA) injury in rats increases impulsivity, decreases dopaminergic innervation in the olfactory tubercle and generates white matter inflammation, tau phosphorylation and degeneration.

Traumatic brain injury (TBI) affects at least 3 M people annually. In humans, repetitive mild TBI (rmTBI) can lead to increased impulsivity and may be associated with chronic traumatic encephalopathy. To better understand the relationship between repetitive TBI (rTBI), impulsivity and neuropathology, we used CHIMERA (Closed-Head Injury Model of Engineered Rotational Acceleration) to deliver five TBIs to rats, which were continuously assessed for trait impulsivity using the delay discounting task and for neuropathology at endpoint. Compared to sham controls, rats with rTBI displayed progressive impairment in impulsive choice. Histological analyses revealed reduced dopaminergic innervation from the ventral tegmental area to the olfactory tubercle, consistent with altered impulsivity neurocircuitry. Consistent with diffuse axonal injury generated by CHIMERA, white matter inflammation, tau immunoreactivity and degeneration were observed in the optic tract and corpus callosum. Finally, pronounced grey matter microgliosis was observed in the olfactory tubercle. Our results provide insight into the mechanisms by which rTBI leads to post-traumatic psychiatric-like symptoms in a novel rat TBI platform.

CHIMERA repetitive mild traumatic brain injury induces chronic behavioural and neuropathological phenotypes in wild-type and APP/PS1 mice.

BACKGROUND: The annual incidence of traumatic brain injury (TBI) in the United States is over 2.5 million, with approximately 3-5 million people living with chronic sequelae. Compared with moderate-severe TBI, the long-term effects of mild TBI (mTBI) are less understood but important to address, particularly for contact sport athletes and military personnel who have high mTBI exposure. The purpose of this study was to determine the behavioural and neuropathological phenotypes induced by the Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA) model of mTBI in both wild-type (WT) and APP/PS1 mice up to 8 months post-injury. METHODS: Male WT and APP/PS1 littermates were randomized to sham or repetitive mild TBI (rmTBI; 2 × 0.5 J impacts 24 h apart) groups at 5.7 months of age. Animals were assessed up to 8 months post-injury for acute neurological deficits using the loss of righting reflex (LRR) and Neurological Severity Score (NSS) tasks, and chronic behavioural changes using the passive avoidance (PA), Barnes maze (BM), elevated plus maze (EPM) and rotarod (RR) tasks. Neuropathological assessments included white matter damage; grey matter inflammation; and measures of Aß levels, deposition, and aducanumab binding activity. RESULTS: The very mild CHIMERA rmTBI conditions used here produced no significant acute neurological or motor deficits in WT and APP/PS1 mice, but they profoundly inhibited extinction of fear memory specifically in APP/PS1 mice over the 8-month assessment period. Spatial learning and memory were affected by both injury and genotype. Anxiety and risk-taking behaviour were affected by injury but not genotype. CHIMERA rmTBI induced chronic white matter microgliosis, axonal injury and astrogliosis independent of genotype in the optic tract but not the corpus callosum, and it altered microgliosis in APP/PS1 amygdala and hippocampus. Finally, rmTBI did not alter long-term tau, Aß or amyloid levels, but it increased aducanumab binding activity. CONCLUSIONS: CHIMERA is a useful model to investigate the chronic consequences of rmTBI, including behavioural abnormalities consistent with features of post-traumatic stress disorder and inflammation of both white and grey matter. The presence of human Aß greatly modified extinction of fear memory after rmTBI.

Long-term deficits in risky decision-making after traumatic brain injury on a rat analog of the Iowa gambling task.

Traumatic brain injury (TBI) affects 2.8 million people annually in the United States, with significant populations suffering from ongoing cognitive dysfunction. Impairments in decision-making can have major implications for patients and their caregivers, often enduring for years to decades, yet are rarely explored in experimental TBI. In the current study, the Rodent Gambling Task (RGT), an Iowa Gambling Task analog, was used to assess risk-based decision-making and motor impulsivity after TBI. During testing, rats chose between options associated with different probabilities of reinforcement (sucrose) or punishment (timeout). To determine effects of TBI on learned behaviors versus the learning process, rats were trained either before, or after, a bilateral frontal controlled cortical impact TBI, and then assessed for 12 weeks. To evaluate the degree to which monoamine systems, such as dopamine, were affected by TBI, rats were given an amphetamine challenge, and behavior recorded. Injury immediately and chronically decreased optimal decision-making, and biased rats towards both riskier, and safer (but suboptimal) choices, regardless of prior learning history. TBI also increased motor impulsivity across time, reflecting ongoing neural changes. Despite these similarities in trained and acquisition rats, those that learned the task after injury demonstrated reduced effects of amphetamine on optimal decision-making, suggesting a lesser role of monoamines in post-injury learning. Amphetamine also dose-dependently reduced motor impulsivity in injured rats. This study opens up the investigation of psychiatric-like dysfunction in animal models of TBI and tasks such as the RGT will be useful in identifying therapeutics for the chronic post-injury period.

A Rational Structured Epitope Defines a Distinct Subclass of Toxic Amyloid-beta Oligomers.

Oligomers of amyloid-ß (AßO) are deemed key in synaptotoxicity and amyloid seeding of Alzheimer's disease (AD). However, the heterogeneous and dynamic nature of AßO and inadequate markers for AßO subtypes have stymied effective AßO identification and therapeutic targeting in vivo. We identified an AßO-subclass epitope defined by differential solvent orientation of the lysine 28 side chain in a constrained loop of serine-asparagine-lysine (cSNK), rarely displayed in molecular dynamics simulations of monomer and fibril ensembles. A mouse monoclonal antibody targeting AßOcSNK recognizes ∼50-60 kDa SDS-resistant soluble Aß assemblages in AD brain and prolongs the lag phase of Aß aggregation in vitro. Acute peripheral infusion of a murine IgG1 anti-AßOcSNK in two AD mouse models reduced soluble brain Aß aggregates by 20-30%. Chronic cSNK peptide immunization of APP/PS1 mice engendered an anti-AßOcSNK IgG1 response without epitope spreading to Aß monomers or fibrils and was accompanied by preservation of global PSD95 expression and improved cued fear memory. Our data indicate that the oligomer subtype AßOcSNK participates in synaptotoxicity and propagation of Aß aggregation in vitro and in vivo.

Age at injury and genotype modify acute inflammatory and neurofilament-light responses to mild CHIMERA traumatic brain injury in wild-type and APP/PS1 mice.

Peak incidence of traumatic brain injury (TBI) occurs in both young and old individuals, and older age at injury is associated with worse outcome and poorer recovery. Moderate-severe TBI is a reported risk factor for dementia, including Alzheimer's disease (AD), but whether mild TBI (mTBI) alters AD pathogenesis is not clear. To delineate how age at injury and predisposition to amyloid formation affect the acute response to mTBI, we used the Closed Head Impact Model of Engineered Rotational Acceleration (CHIMERA) model of TBI to induce two mild injuries in wild-type (WT) and APP/PS1 mice at either 6 or 13months of age and assessed behavioural, histological and biochemical changes up to 14days post-injury. Age at injury did not alter acute behavioural responses to mTBI, including measures of neurological status, motor performance, spatial memory, fear, or anxiety, in either strain. Young APP/PS1 mice showed a subtle and transient increase in diffuse Aß deposits after injury, whereas old APP/PS1 mice showed decreased amyloid deposits, without significant alterations in total soluble or insoluble Aß levels at either age. Age at injury and genotype showed complex responses with respect to microglial and cytokine outcomes, where post-injury neuroinflammation is increased in old WT mice but attenuated in old APP/PS1 mice. Intriguingly, silver staining confirmed axonal damage in both strains and ages, yet only young WT and APP/PS1 mice showed neurofilament-positive axonal swellings after mTBI, as this response was almost entirely attenuated in old mice. Plasma neurofilament-light levels were significantly elevated after injury only in young APP/PS1 mice. This study suggests that mild TBI has minimal effects on Aß metabolism, but that age and genotype can each modify acute outcomes related to white matter injury.

Frontal Traumatic Brain Injury Increases Impulsive Decision Making in Rats: A Potential Role for the Inflammatory Cytokine Interleukin-12.

Traumatic brain injury (TBI) is associated with the development of numerous psychiatric diseases. Of particular concern for TBI patients is the impact of chronic impulsivity on daily functioning. Despite the scope of the human problem, little has been done to address impulsivity in animal models of brain injury. In the current study, we examined the effects of either a severe or a milder bilateral frontal controlled cortical impact injury on impulsivity using the Delay Discounting Task (DDT), in which preference for smaller-sooner over larger-later rewards is indicative of greater impulsive choice. Both milder and severe TBI caused a significant, chronic increase in impulsive decision making. Despite these pronounced changes in performance of the DDT, memory function, as assessed by the Morris Water Maze, was not impaired in more mildly injured rats and only transiently impacted in the severe TBI group. Whereas a significant lesion was only evident in severely injured rats, analysis of cytokine levels within the frontal cortex revealed a selective increase in interleukin (IL)-12 that was associated with the magnitude of the change in impulsive choice caused by both milder and severe TBI. These findings suggest that tissue loss alone cannot explain the increased impulsivity observed, and that inflammatory pathways mediated by IL-12 may be a contributing factor. The findings from this study highlight the sensitivity of sophisticated behavioral measures designed to assess neuropsychiatric dysfunction in the detection of TBI-induced cognitive impairments and their utility in identifying potential mechanistic pathways and therapeutic targets.

Defining the biomechanical and biological threshold of murine mild traumatic brain injury using CHIMERA (Closed Head Impact Model of Engineered Rotational Acceleration).

CHIMERA (Closed Head Impact Model of Engineered Rotational Acceleration) is a recently described animal model of traumatic brain injury (TBI) that primarily produces diffuse axonal injury (DAI) characterized by white matter inflammation and axonal damage. CHIMERA was specifically designed to reliably generate a variety of TBI severities using precise and quantifiable biomechanical inputs in a nonsurgical user-friendly platform. The objective of this study was to define the lower limit of single impact mild TBI (mTBI) using CHIMERA by characterizing the dose-response relationship between biomechanical input and neurological, behavioral, neuropathological and biochemical outcomes. Wild-type male mice were subjected to a single CHIMERA TBI using six impact energies ranging from 0.1 to 0.7J, and post-TBI outcomes were assessed over an acute period of 14days. Here we report that single TBI using CHIMERA induces injury dose- and time-dependent changes in behavioral and neurological deficits, axonal damage, white matter tract microgliosis and astrogliosis. Impact energies of 0.4J or below produced no significant phenotype (subthreshold), 0.5J led to significant changes for one or more phenotypes (threshold), and 0.6 and 0.7J resulted in significant changes in all outcomes assessed (mTBI). We further show that linear head kinematics are the most robust predictors of duration of unconsciousness, severity of neurological deficits, white matter injury, and microgliosis following single TBI. Our data extend the validation of CHIMERA as a biofidelic animal model of DAI and establish working parameters to guide future investigations of the mechanisms underlying axonal pathology and inflammation induced by mechanical trauma.

Chronic Exposure to Androgenic-Anabolic Steroids Exacerbates Axonal Injury and Microgliosis in the CHIMERA Mouse Model of Repetitive Concussion.

Concussion is a serious health concern. Concussion in athletes is of particular interest with respect to the relationship of concussion exposure to risk of chronic traumatic encephalopathy (CTE), a neurodegenerative condition associated with altered cognitive and psychiatric functions and profound tauopathy. However, much remains to be learned about factors other than cumulative exposure that could influence concussion pathogenesis. Approximately 20% of CTE cases report a history of substance use including androgenic-anabolic steroids (AAS). How acute, chronic, or historical AAS use may affect the vulnerability of the brain to concussion is unknown. We therefore tested whether antecedent AAS exposure in young, male C57Bl/6 mice affects acute behavioral and neuropathological responses to mild traumatic brain injury (TBI) induced with the CHIMERA (Closed Head Impact Model of Engineered Rotational Acceleration) platform. Male C57Bl/6 mice received either vehicle or a cocktail of three AAS (testosterone, nandrolone and 17α-methyltestosterone) from 8-16 weeks of age. At the end of the 7th week of treatment, mice underwent two closed-head TBI or sham procedures spaced 24 h apart using CHIMERA. Post-repetitive TBI (rTBI) behavior was assessed for 7 d followed by tissue collection. AAS treatment induced the expected physiological changes including increased body weight, testicular atrophy, aggression and downregulation of brain 5-HT1B receptor expression. rTBI induced behavioral deficits, widespread axonal injury and white matter microgliosis. While AAS treatment did not worsen post-rTBI behavioral changes, AAS-treated mice exhibited significantly exacerbated axonal injury and microgliosis, indicating that AAS exposure can alter neuronal and innate immune responses to concussive TBI.

Vitamins and nutrients as primary treatments in experimental brain injury: Clinical implications for nutraceutical therapies.

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.

Merging pathology with biomechanics using CHIMERA (Closed-Head Impact Model of Engineered Rotational Acceleration): a novel, surgery-free model of traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) is a major health care concern that currently lacks any effective treatment. Despite promising outcomes from many preclinical studies, clinical evaluations have failed to identify effective pharmacological therapies, suggesting that the translational potential of preclinical models may require improvement. Rodents continue to be the most widely used species for preclinical TBI research. As most human TBIs result from impact to an intact skull, closed head injury (CHI) models are highly relevant, however, traditional CHI models suffer from extensive experimental variability that may be due to poor control over biomechanical inputs. Here we describe a novel CHI model called CHIMERA (Closed-Head Impact Model of Engineered Rotational Acceleration) that fully integrates biomechanical, behavioral, and neuropathological analyses. CHIMERA is distinct from existing neurotrauma model systems in that it uses a completely non-surgical procedure to precisely deliver impacts of prescribed dynamic characteristics to a closed skull while enabling kinematic analysis of unconstrained head movement. In this study, we characterized head kinematics as well as functional, neuropathological, and biochemical outcomes up to 14d following repeated TBI (rTBI) in adult C57BL/6 mice using CHIMERA. RESULTS: Head kinematic analysis showed excellent repeatability over two closed head impacts separated at 24h. Injured mice showed significantly prolonged loss of righting reflex and displayed neurological, motor, and cognitive deficits along with anxiety-like behavior. Repeated TBI led to diffuse axonal injury with extensive microgliosis in white matter from 2-14d post-rTBI. Injured mouse brains also showed significantly increased levels of TNF-α and IL-1ß and increased endogenous tau phosphorylation. CONCLUSIONS: Repeated TBI using CHIMERA mimics many of the functional and pathological characteristics of human TBI with a reliable biomechanical response of the head. This makes CHIMERA well suited to investigate the pathophysiology of TBI and for drug development programs.

Simple tone discriminations are disrupted following experimental frontal traumatic brain injury in rats.

PRIMARY OBJECTIVE: To assess cognitive deficits in a rat model of brain injury. RESEARCH DESIGN: Cognitive deficits are some of the most pervasive and enduring symptoms of frontal traumatic brain injury (TBI) in human patients. In animal models, the assessment of cognitive deficits from TBI has primarily been limited to tests of spatial learning. Recently, simple discrimination performance has been shown to be sensitive to frontal brain damage. The current study provides a detailed characterization of deficits in a two-choice tone discrimination following a bilateral frontal controlled cortical impact injury. METHODS AND PROCEDURES: Rats were trained on a two-tone discrimination task in a standard operant chamber, then either a frontal brain injury was delivered or sham procedures performed. Following recovery, they were re-tested on the discrimination task and then tested on a reversal of the discrimination. MAIN OUTCOMES AND RESULTS: Frontal injury caused substantial deficits in responding and discrimination accuracy as well as an increase in side bias. CONCLUSIONS: Based on the outcomes seen in this study, discrimination and other operant tasks may provide a sensitive tool to assess the effect of therapeutic agents on cognitive deficits in animal models, which could lead to improved characterization of deficits and yield an improved assessment tool to aid in drug discovery.

The dig task: a simple scent discrimination reveals deficits following frontal brain damage.

Cognitive impairment is the most frequent cause of disability in humans following brain damage, yet the behavioral tasks used to assess cognition in rodent models of brain injury is lacking. Borrowing from the operant literature our laboratory utilized a basic scent discrimination paradigm in order to assess deficits in frontally-injured rats. Previously we have briefly described the Dig task and demonstrated that rats with frontal brain damage show severe deficits across multiple tests within the task. Here we present a more detailed protocol for this task. Rats are placed into a chamber and allowed to discriminate between two scented sands, one of which contains a reinforcer. The trial ends after the rat either correctly discriminates (defined as digging in the correct scented sand), incorrectly discriminates, or 30 sec elapses. Rats that correctly discriminate are allowed to recover and consume the reinforcer. Rats that discriminate incorrectly are immediately removed from the chamber. This can continue through a variety of reversals and novel scents. The primary analysis is the accuracy for each scent pairing (cumulative proportion correct for each scent). The general findings from the Dig task suggest that it is a simple experimental preparation that can assess deficits in rats with bilateral frontal cortical damage compared to rats with unilateral parietal damage. The Dig task can also be easily incorporated into an existing cognitive test battery. The use of more tasks such as this one can lead to more accurate testing of frontal function following injury, which may lead to therapeutic options for treatment. All animal use was conducted in accordance with protocols approved by the Institutional Animal Care and Use Committee.

A discrimination task used as a novel method of testing decision-making behavior following traumatic brain injury.

Traumatic brain injury (TBI) results in a multitude of deficits following injury. Some of the most pervasive in humans are the changes that affect frontally-mediated cognitive functioning, such as decision making. The assessment of decision-making behavior in rodents has been extensively tested in the field of the experimental analysis of behavior. However, due to the narrow therapeutic window following TBI, time-intensive operant paradigms are rarely incorporated into the battery of tests traditionally used, the majority of which assess motor and sensory functioning. The cognitive measures that are used are frequently limited to memory and do not account for changes in decision-making behavior. The purpose of the present study was to develop a simplified discrimination task that can assess deficits in decision-making behavior in rodents. For the task, rats were required to dig in cocoa-scented sand (versus unscented sand) for a reinforcer. Rats were given 12 sessions per day until a criterion level of 80% accuracy for 3 days straight was reached. Once the criterion was achieved, cortical contusion injuries were induced (frontal, parietal, or sham). Following a recovery period, the rats were re-tested on cocoa versus unscented sand. Upon reaching criterion, a reversal discrimination was evaluated in which the reinforcer was placed in unscented sand. Finally, a novel scent discrimination (basil versus coffee with basil reinforced), and a reversal (coffee) were evaluated. The results indicated that the Dig task is a simple experimental preparation that can be used to assess deficits in decision-making behavior following TBI.