Traumatic brain injury (TBI) represents a significant cause of death and disability in industrialized countries. Of particular importance to patients the chronic effect that TBI has on cognitive function. Therapeutic strategies have been difficult to evaluate because of the complexity of injuries and variety of patient presentations within a TBI population. However, pharmacotherapies targeting dopamine (DA) have consistently shown benefits in attention, behavioral outcome, executive function, and memory. Still it remains unclear what aspect of TBI pathology is targeted by DA therapies and what time-course of treatment is most beneficial for patient outcomes. Fortunately, ongoing research in animal models has begun to elucidate the pathophysiology of DA alterations after TBI. The purpose of this review is to discuss clinical and experimental research examining DAergic therapies after TBI, which will in turn elucidate the importance of DA for cognitive function/dysfunction after TBI as well as highlight the areas that require further study.

Persistent cognitive deficits are one of the most important sequelae of head injury in humans. In an effort to model some of the structural and neuropharmacological changes that occur in chronic postinjury brains, we examined the longitudinal effects of moderate vertical controlled cortical impact (CCI) on place learning and memory using the Morris water maze (MWM) test, morphology, and vesicular acetylcholine (ACh) transporter (VAChT) and muscarinic receptor subtype 2 (M2) immunohistochemistry. Vertical CCI (left parietal cortex, 4 m/sec, 2.5 mm; n = 10) or craniotomy (sham) was produced in male Sprague-Dawley rats (n = 10). Place learning was tested at 2 weeks, 4 weeks, 3 months, 6 months, and 12 months postinjury with the escape platform in a different maze quadrant for each time point. At each interval, rats received 5 days of water maze acquisition (latency to find hidden platform), a probe trial to measure place memory, and 2 days of visible platform trials to control for nonspecific deficits. At 3 weeks, half the animals were sacrificed for histology. At these injury parameters, CCI produced no significant differences in place learning between injured and sham rats at 2 weeks, 4 weeks, or 6 months after injury. However, at 3 and 12 months, the injured rats took significantly longer to find the hidden platform than the sham rats. Probe trial performance differed only at 12 months postinjury between injured (25.73+/-2.1%, standard error of the mean) and sham rats (44.09+/-7.0%, p < 0.05). The maze deficits at 1 year were not due to a worsening of performance, but may have resulted from a reduced ability of injured rats to benefit from previous water maze experience. Hemispheric loss of 30.4+/-5.5 mm3 was seen at 3 weeks after injury (versus respective sham). However, hemispheric loss almost doubled by 1 year after injury (51.5+/-8.5 mm3, p < 0.05 versus all other groups). Progressive tissue loss was also reflected by a three- to fourfold increase in ipsilateral ventricular volume between 3 weeks and 1 year after injury. At 1 year after injury, immunostaining for VAChT was dramatically increased in all sectors of the hippocampus and cortex after injury. Muscarinic receptor subtype 2 (M2) immunoreactivity was dramatically decreased in the ipsilateral hippocampus. This suggests a compensatory response of cholinergic neurons to increase the efficiency of ACh neurotransmission. Moderate CCI in rats produces subtle MWM performance deficits accompanied by persistent alteration in M2 and VAChT immunohistochemistry and progressive tissue atrophy. The inability of injured rats to benefit from repeated exposures to the MWM may represent a deficit in procedural memory that is independent of changes in hippocampal cholinergic systems.

Experimental traumatic brain injury (TBI) studies report the neuroprotective effects of female sex steroids on multiple mechanisms of injury, with the clinical assumption that women have hormonally mediated neuroprotection because of the endogenous presence of these hormones. Other literature indicates that testosterone may exacerbate injury. Further, stress hormone abnormalities that accompany critical illness may both amplify or blunt sex steroid levels. To better understand the role of sex steroid exposure in mediating TBI, we 1) characterized temporal profiles of serum gonadal and stress hormones in a population with severe TBI during the acute phases of their injury; and 2) used a biological systems approach to evaluate these hormones as biomarkers predicting global outcome. The study population was 117 adults (28 women; 89 men) with severe TBI. Serum samples (n = 536) were collected for 7 days post-TBI for cortisol, progesterone, testosterone, estradiol, luteinizing hormone (LH), and follicle-stimulating hormone (FSH). Hormone data were linked with clinical data, including acute care mortality and Glasgow Outcome Scale (GOS) scores at 6 months. Hormone levels after TBI were compared to those in healthy controls (n = 14). Group based trajectory analysis (TRAJ) was used to develop temporal hormone profiles that delineate distinct subpopulations in the cohort. Structural equations models were used to determine inter-relationships between hormones and outcomes within a multivariate model. Compared to controls, acute serum hormone levels were significantly altered after severe TBI. Changes in the post-TBI adrenal response and peripheral aromatization influenced hormone TRAJ profiles and contributed to the abnormalities, including increased estradiol in men and increased testosterone in women. In addition to older age and greater injury severity, increased estradiol and testosterone levels over time were associated with increased mortality and worse global outcome for both men and women. These findings represent a paradigm shift when thinking about the role of sex steroids in neuroprotection clinically after TBI.

Cognitive impairments are pervasive and persistent sequelae of human traumatic brain injury (TBI). In vivo models of TBI, such as the controlled cortical impact (CCI) and fluid percussion (FP), are utilized extensively to produce deficits reminiscent of those seen clinically with the hope that empirical study will lead to viable therapeutic interventions. Both CCI and FP produce spatial learning acquisition deficits, but only the latter has been reported to impair working memory in rats tested in the Morris water maze (MWM). We hypothesized that a CCI injury would impair working memory similarly to that produced by FP, and that delayed and chronic treatment with the D2 receptor agonist bromocriptine would attenuate both working memory and spatial learning acquisition deficits. To test these hypotheses, isoflurane-anesthetized adult male rats received either a CCI (2.7 mm deformation, 4 m/sec) or sham injury, and 24 h later were administered bromocriptine (5 mg/kg, i.p.) or vehicle, with continued daily injections until all behavioral assessments were completed. Motor function was assessed on beam balance and beam walking tasks on postoperative days 1-5 and cognitive function was evaluated in the MWM on days 11-15 for working memory (experiment 1) and on days 14-18 for spatial learning acquisition (experiment 2). Histological examination (hippocampal CA1 and CA3 cell loss/survival and cortical lesion volume) was conducted 4 weeks after surgery. All injured groups exhibited initial impairments in motor function, working memory, and spatial learning acquisition. Bromocriptine did not affect motor function, but did ameliorate working memory and significantly attenuated spatial acquisition deficits relative to the injured vehicle-treated controls. Additionally, the injured bromocriptine-treated group exhibited significantly more morphologically intact CA3 neurons than the injured vehicle-treated group (55.60 +/- 3.10% vs. 38.34 +/- 7.78% [p = 0.03]). No significant differences were observed among TBI groups in CA1 cell survival (bromocriptine, 40.26 +/- 4.74% vs. vehicle, 29.13 +/- 6.63% [p = 0.14]) or cortical lesion volume (bromocriptine, 17.78 +/- 0.62 mm3 vs. vehicle, 19.01 +/- 1.49 mm3 [p > 0.05]). These data reveal that CCI produces working memory deficits in rats that are similar to those observed following FP, and that the delayed and chronic bromocriptine treatment regimen conferred cognitive and neural protection after TBI.

Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) has emerged as a novel powerful MS methodology that has the ability to generate both molecular and spatial information within a tissue section. Application of this technology as a new type of biochemical lipid microscopy may lead to new discoveries of the lipid metabolism and biomarkers associated with area-specific alterations or damage under stress/disease conditions such as traumatic brain injury or acute lung injury, among others. However there are limitations in the range of what it can detect as compared with liquid chromatography-MS (LC-MS) of a lipid extract from a tissue section. The goal of the current work was to critically consider remarkable new opportunities along with the limitations and approaches for further improvements of MALDI-MSI. Based on our experimental data and assessments, improvements of the spectral and spatial resolution, sensitivity and specificity towards low abundance species of lipids are proposed. This is followed by a review of the current literature, including methodologies that other laboratories have used to overcome these challenges.

BONDI, C.O., B.D. Semple, L.J. Noble-Haeusslein, N.D. Osier, S.W. Carlson, C.E. Dixon, C.C. Giza and A.E. Kline. Found in translation: understanding the biology and behavior of experimental traumatic brain injury. NEUROSCI BIOBEHAV REV. The aim of this review is to discuss in greater detail the topics covered in the recent symposium entitled “Traumatic brain injury: laboratory and clinical perspectives,” presented at the 2014 International Behavioral Neuroscience Society annual meeting. Herein we review contemporary laboratory models of traumatic brain injury (TBI) including common assays for sensorimotor and cognitive behavior. New modalities to evaluate social behavior after injury to the developing brain, as well as the attentional set-shifting test (AST) as a measure of executive function in TBI, will be highlighted. Environmental enrichment (EE) will be discussed as a preclinical model of neurorehabilitation, and finally, an evidence-based approach to sports-related concussion will be considered. The review consists predominantly of published data, but some discussion of ongoing or future directions is provided.

We recently reported that the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) attenuated traumatic brain injury (TBI)-induced cognitive deficits and histopathology. However, 8-OH-DPAT also produced mild hypothermia (Hypo), which may have contributed to the benefit. To clarify this issue, we conducted an experiment similar to the previous, but included an 8-OH-DPAT group that was maintained at 37 +/- 0.5 degrees C (normothermia; Normo). Isoflurane-anesthetized rats received either a cortical impact (2.7-mm deformation at 4 m/sec) or sham injury and then were randomly assigned to two saline (Sham/Vehicle, n = 5; Injury/Vehicle, n = 10) or three 8-OH-DPAT (Sham/DPAT, n = 5; Injury/DPAT + Normo, n = 10; Injury/DPAT + Hypo, n = 10) groups. 8-OH-DPAT (0.5 mg/kg) or a comparable volume of saline was administered intraperitoneally 15 min after cortical impact or sham injury. Core temperatures were taken prior to treatment and every 15 min thereafter for 2 h. Function was assessed by established motor and cognitive tasks on post-operative days 1-5 and 14-20, respectively. Hippocampal CA1/CA3 cell survival and cortical lesion volume were quantified at 4 weeks. Both the Injury/DPAT + Normo and Injury/DPAT + Hypo groups exhibited enhanced cognitive performance (spatial acquisition and retention) and reduced histopathology (CA3 cell loss and cortical lesion volume) versus the Injury/ Vehicle group (P < 0.05), but did not differ from one another despite a rapid (15 min), mild (34.4-34.9 degrees C), and transient (~1 h) hypothermic effect in the latter. These data confirm that a single systemic administration of 8-OH-DPAT confers neurological protection after TBI, and demonstrate that the beneficial effect is not mediated by concomitant hypothermia. The mechanisms for the protective effects of 8-OH-DPAT after TBI require further inquiry.

Objective-Develop a clinically relevant model of pediatric asphyxial cardiopulmonary arrest in rats. Design-Prospective interventional study. Setting-University research laboratory.Subjects-Post-natal day (PND) 16-18 rats.Interventions-Anesthetized rats were endotracheally intubated and mechanically ventilated, and vascular catheters were inserted. Vecuronium was administered and the ventilator was disconnected from the rats for 8 min, whereupon rats were resuscitated with epinephrine, sodium bicarbonate, and chest compressions until spontaneous circulation returned. Shams underwent all procedures except asphyxia.Measurements and Main Results-Asphyxial arrest typically occurred by 1 min after the ventilator was disconnected. Return of spontaneous circulation typically occurred <30 sec after resuscitation. An isoelectric electroencephalograph was observed for 30 min after asphyxia and rats remained comatose for 12-24 h. Survival rate in rats after asphyxia was 75%. Motor function measured using beam balance and inclined plane tests was impaired on d 1 and 2, but recovered by d 3, in rats after asphyxia vs. sham injury (n=9/group; P<0.05). Spatial memory acquisition measured using the Morris-water maze on d 7-14 and 28-35 was also impaired in rats after asphyxia vs. sham injury (total latency 379±28 vs. 501±40 sec, respectfully; n=9/group; P<0.05). CA1 hippocampal neuron survival after asphyxia was 39-43% (n=9/group; P<0.001 vs. sham). DNA fragmentation was detected in CA1 hippocampal neurons bilaterally in separate rats on d 3-7 after asphyxia (n=3-4/group). Neurodegeneration detected using Fluorojade-B was seen in bilateral CA1 hippocampi and layer III cortical neurons 3-7 d after asphyxia, with persistent neurodegeneration in CA1 hippocampus detected up to 5 wks after asphyxia. Evidence of DNA or cellular injury was not detected in sham rats.