Cole Vonder Haar

The potential for animal models to provide insight into mild traumatic brain injury: Translational challenges and strategies.

HighlightsMild traumatic brain injuries (mTBI) are common and in need of scientific research.There are confounding variables and limitations in mTBI patient studies.The use of animal models of may complement mTBI patient studies.Strengths/limitations of each model should be considered in study design and interpretation.Combined patient and animal model approach may allow for evidence‐based translation to clinical management. ABSTRACT Mild traumatic brain injury (mTBI) is a common health problem. There is tremendous variability and heterogeneity in human mTBI, including mechanisms of injury, biomechanical forces, injury severity, spatial and temporal pathophysiology, genetic factors, pre‐injury vulnerability and resilience factors, and clinical outcomes. Animal models greatly reduce this variability and heterogeneity, and provide a means to study mTBI in a rigorous, controlled, and efficient manner. Rodent models, in particular, are time‐ and cost‐efficient, and they allow researchers to measure morphological, cellular, molecular, and behavioral variables in a single study. However, inter‐species differences in anatomy, morphology, metabolism, neurobiology, and lifespan create translational challenges. Although the term “mild” TBI is used often in the pre‐clinical literature, clearly defined criteria for mild, moderate, and severe TBI in animal models have not been agreed upon. In this review, we introduce current issues facing the mTBI field, summarize the available research methodologies and previous studies in mTBI animal models, and discuss how a translational research approach may be useful in advancing our understanding and management of mTBI.

Continuous nicotinamide administration improves behavioral recovery and reduces lesion size following bilateral frontal controlled cortical impact injury

Previous research has demonstrated considerable preclinical efficacy of nicotinamide (NAM; vitamin B(3)) in animal models of TBI with systemic dosing at 50 and 500 mg/kg yielding improvements on sensory, motor, cognitive and histological measures. The current study aimed to utilize a more specific dosing paradigm in a clinically relevant delivery mechanism: continuously secreting subcutaneous pumps. A bilateral frontal controlled cortical impact (CCI) or sham surgery was performed and rats were treated with NAM (150 mg/kg day) or saline (1 ml/kg) pumps 30 min after CCI, continuing until seven days post-CCI. Rats were given a loading dose of NAM (50mg/kg) or saline (1 ml/kg) following pump implant. Rats received behavioral testing (bilateral tactile adhesive removal, locomotor placing task and Morris water maze) starting on day two post-CCI and were sacrificed at 31 days post-CCI and brains were stained to examine lesion size. NAM-treated rats had reductions in sensory, motor and cognitive behavioral deficits compared to vehicle-treated rats. Specifically, NAM-treated rats significantly improved on the bilateral tactile adhesive removal task, locomotor placing task and the reference memory paradigm of the Morris water maze. Lesion size was also significantly reduced in the NAM-treated group. The results from this study indicate that at the current dose, NAM produces beneficial effects on recovery from a bilateral frontal brain injury and that it may be a relevant compound to be explored in human studies.

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.

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.

Comparison of the Effect of Minocycline and Simvastatin on Functional Recovery and Gene Expression in a Rat Traumatic Brain Injury Model

The goal of this study was to compare the effects of minocycline and simvastatin on functional recovery and brain gene expression after a cortical contusion impact (CCI) injury. Dosage regimens were designed to provide serum concentrations in a rat model in the range obtained with clinically approved doses; minocycline 60 mg/kg q12h and simvastatin 10 mg/kg q12h for 72 h. Functional recovery was assessed using motor and spatial learning tasks and neuropathological measurements. Microarray-based transcriptional profiling was used to determine the effect on gene expression at 24 h, 72 h, and 7 days post-CCI. Gene Ontology analysis (GOA) was used to evaluate the effect on relevant biological pathways. Both minocycline and simvastatin improved fine motor function, but not gross motor or cognitive function. Minocycline modestly decreased lesion size with no effect of simvastatin. At 24 h post-CCI, GOA identified a significant effect of minocycline on chemotaxis, blood circulation, immune response, and cell to cell signaling pathways. Inflammatory pathways were affected by minocycline only at the 72 h time point. There was a minimal effect of simvastatin on gene expression 24 h after injury, with increasing effects at 72 h and 7 days. GOA identified a significant effect of simvastatin on inflammatory response at 72 h and 7 days. In conclusion, treatment with minocycline and simvastatin resulted in significant effects on gene expression in the brain reflecting adequate brain penetration without producing significant neurorestorative effects.

The Use of Nicotinamide as a Treatment for Experimental Traumatic Brain Injury and Stroke: A Review and Evaluation

Traumatic Brain Injury (TBI) and stroke are leading causes of neurological dysfunction and are major health concerns worldwide. Much research has been conducted on the processes at work in TBI and stroke; however, to date no pharmaceutical treatments have been shown to be effective in treating human clinical TBI and only one drug has been approved for human stroke treatment. Thus, many laboratories have begun to investigate organic compounds such as vitamins and other nutrients. Specifically, nicotinamide (vitamin B3) has been studied in the laboratory to assess its effectiveness as a treatment following TBI or stroke. This review evaluates the experimental evidence for the use of nicotinamide to treat brain injury. Based on the evidence from animal models, there is considerable potential for the use of nicotinamide to treat TBI and stroke. However there are still some factors that need to be further investigated before considering clinical trials.

Chronic folic acid administration confers no treatment effects in either a high or low dose following unilateral controlled cortical impact injury in the rat

PURPOSE Traumatic brain injury (TBI) is a major health concern today and effective treatments must be developed in order to combat the numerous TBIs that occur each year. Multiple b-vitamins have been shown to have neuroprotective effects, however, folic acid (B9) has not been widely studied. The current study examined two different doses in a rodent model of controlled cortical impact (CCI) TBI. METHODS Sham procedures or a unilateral parietal controlled cortical impact injury was induced. Rats were administered either vehicle or folic acid in an 80 μg/kg or 800 μg/kg dose. Rats were tested on the bilateral tactile adhesive removal task, rotarod task and the Morris water maze. Brains were examined to determine lesion size and neuronal loss. RESULTS Neither of the folic acid-treated groups showed improvement on any behavioral task or anatomical measure post-CCI and the high dose group had increased neuronal loss compared to the vehicle. Administration of the high dose in sham animals resulted in some behavioral dysfunction and significant neuronal loss. CONCLUSIONS The results from this study suggest that folic acid may not represent an effective avenue for treatment and that higher doses may actually be detrimental following TBI.

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 paradigm1-4in 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 task5. 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.

Successive bilateral frontal controlled cortical impact injuries show behavioral savings.

Traumatic brain injuries (TBIs) affect millions of people each year. Research investigating repeated or serial damage in the form of lesions indicates that behavioral deficits are reduced in animals given sequential lesions separated by a sufficient period of recovery. In the lesion literature, this phenomenon is known as the serial lesion effect (SLE). Although the SLE phenomenon is established in the lesion literature, it has not been thoroughly investigated under current models of brain injury. In the current study, a controlled cortical impact of the bilateral frontal cortex was performed in either a single procedure or a serial procedure separated by two weeks. Rats were tested on the Morris water maze, bilateral tactile adhesive removal task, rotarod and Barnes maze task to determine behavioral deficits. Histology was performed to determine lesion size and astrocyte and microglial response. A serial lesion effect was demonstrated across a majority of the behavioral tasks. However, histological analyses did not suggest a clear mechanistic link to the behavioral phenomena. This is the first study to demonstrate the SLE in a model of TBI, suggesting that behavioral deficits may actually be reduced in repeated head injuries, given an adequate time window between injuries.

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

Abstract 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.