A bridge to recovery: Acute amantadine prior to environmental enrichment after brain trauma augments cognitive benefit.

Environmental enrichment (EE) facilitates motor and cognitive recovery after traumatic brain injury (TBI). Historically, EE has been provided immediately and continuously after TBI, but this paradigm does not model the clinic where rehabilitation is typically not initiated until after critical care. Yet, treating TBI early may facilitate recovery. Hence, we sought to provide amantadine (AMT) as a bridge therapy before commencing EE. It was hypothesized that bridging EE with AMT would augment motor and cognitive benefits. Anesthetized adult male rats received a cortical impact (2.8 mm deformation at 4 m/s) or sham surgery and then were housed in standard (STD) conditions where they received intraperitoneal AMT (10 mg/kg or 20 mg/kg) or saline vehicle (VEH; 1 mL/kg) beginning 24 h after surgery and once daily during the 6-day bridge phase or once daily for 19 days for the non-bridge groups (i.e., continuously STD-housed) to compare the effects of acute AMT plus EE vs. chronic AMT alone. Abbreviated EE, which was presented to closer emulate clinical rehabilitation (e.g., 6 h/day), began on day 7 for the AMT bridge and chronic EE groups. Motor (beam-walking) and cognition (acquisition of spatial learning and memory) were assessed on days 7-11 and 14-19, respectively. Cortical lesion volume and hippocampal cell survival were quantified on day 21. EE, whether provided in combination with VEH or AMT, and AMT (20 mg/kg) + STD, benefitted motor and cognition vs. the STD-housed VEH and AMT (10 mg/kg) groups (p < 0.05). The AMT (20 mg/kg) + EE group performed better than the VEH + EE, AMT (10 mg/kg) + EE, and AMT (20 mg/kg) + STD groups in the acquisition of spatial learning (p < 0.05) but did not differ in motor function (p > 0.05). All groups receiving EE exhibited decreased cortical lesion volumes and increased CA3 neuron survival relative to the STD-housed groups (p < 0.05) but did not differ from one another (p > 0.05). The added cognitive benefit achieved by bridging EE with AMT (20 mg/kg) supports the hypothesis that the temporal separation of combinational therapies is more effective after TBI.

Antipsychotic Drugs: The Antithesis to Neurorehabilitation in Models of Pre-Clinical Traumatic Brain Injury.

Sixty-nine million traumatic brain injuries (TBIs) are reported worldwide each year, and, of those, close to 3 million occur in the United States. In addition to neurobehavioral and cognitive deficits, TBI induces other maladaptive behaviors, such as agitation and aggression, which must be managed for safe, accurate assessment and effective treatment of the patient. The use of antipsychotic drugs (APDs) in TBI is supported by some expert guidelines, which suggests that they are an important part of the pharmacological armamentarium to be used in the management of agitation. Despite the advantages of APDs after TBI, there are significant disadvantages that may not be fully appreciated clinically during decision making because of the lack of a readily available updated compendium. Hence, the aim of this review is to integrate the existing findings and present the current state of APD use in pre-clinical models of TBI. The studies discussed were identified through PubMed and the University of Pittsburgh Library System search strategies and reveal that APDs, particularly those with dopamine2 (D2) receptor antagonism, generally impair the recovery process in rodents of both sexes and, in some instances, attenuate the potential benefits of neurorehabilitation. We believe that the compilation of findings represented by this exhaustive review of pre-clinical TBI + APD models can serve as a convenient source for guiding informed decisions by critical care clinicians and physiatrists contemplating APD use for patients exhibiting agitation.

Neuroprotective potential of intranasally delivered L-myc immortalized human neural stem cells in female rats after a controlled cortical impact injury.

Efficacious stem cell-based therapies for traumatic brain injury (TBI) depend on successful delivery, migration, and engraftment of stem cells to induce neuroprotection. L-myc expressing human neural stem cells (LMNSC008) demonstrate an inherent tropism to injury sites after intranasal (IN) administration. We hypothesize that IN delivered LMNSC008 cells migrate to primary and secondary injury sites and modulate biomarkers associated with neuroprotection and tissue regeneration. To test this hypothesis, immunocompetent adult female rats received either controlled cortical impact injury or sham surgery. LMNSC008 cells or a vehicle were administered IN on postoperative days 7, 9, 11, 13, 15, and 17. The distribution and migration of eGFP-expressing LMNSC008 cells were quantified over 1 mm-thick optically cleared (CLARITY) coronal brain sections from TBI and SHAM controls. NSC migration was observed along white matter tracts projecting toward the hippocampus and regions of TBI. ELISA and Nanostring assays revealed a shift in tissue gene expression in LMNSC008 treated rats relative to controls. LMNSC008 treatment reduced expression of genes and pathways involved in inflammatory response, microglial function, and various cytokines and receptors. Our proof-of-concept studies, although preliminary, support the rationale of using intranasal delivery of LMNSC008 cells for functional studies in preclinical models of TBI and provide support for potential translatability in TBI patients.

Efficacy of a music-based intervention in a preclinical model of traumatic brain injury: An initial foray into a novel and non-pharmacological rehabilitative therapy.

Traumatic brain injury (TBI) causes neurobehavioral and cognitive impairments that negatively impact life quality for millions of individuals. Because of its pernicious effects, numerous pharmacological interventions have been evaluated to attenuate the TBI-induced deficits or to reinstate function. While many such pharmacotherapies have conferred benefits in the laboratory, successful translation to the clinic has yet to be achieved. Given the individual, medical, and societal burden of TBI, there is an urgent need for alternative approaches to attenuate TBI sequelae and promote recovery. Music based interventions (MBIs) may hold untapped potential for improving neurobehavioral and cognitive recovery after TBI as data in normal, non-TBI, rats show plasticity and augmented cognition. Hence, the aim of this study was to test the hypothesis that providing a MBI to adult rats after TBI would improve cognition, neurobehavior, and histological endpoints. Adult male rats received a moderate-to-severe controlled cortical impact injury (2.8 mm impact at 4 m/s) or sham surgery (n = 10-12 per group) and 24 h later were randomized to classical Music or No Music (i.e., ambient room noise) for 3 h/day from 19:00 to 22:00 h for 30 days (last day of behavior). Motor (beam-walk), cognitive (acquisition of spatial learning and memory), anxiety-like behavior (open field), coping (shock probe defensive burying), as well as histopathology (lesion volume), neuroplasticity (BDNF), and neuroinflammation (Iba1, and CD163) were assessed. The data showed that the MBI improved motor, cognitive, and anxiety-like behavior vs. No Music (p's < 0.05). Music also reduced cortical lesion volume and activated microglia but increased resting microglia and hippocampal BDNF expression. These findings support the hypothesis and provide a compelling impetus for additional preclinical studies utilizing MBIs as a potential efficacious rehabilitative therapy for TBI.

Neuroprotective potential of intranasally delivered L-myc immortalized human neural stem cells in female rats after a controlled cortical impact injury.

Efficacious stem cell-based therapies for traumatic brain injury (TBI) depend on successful delivery, migration, and engraftment of stem cells to induce neuroprotection. L-myc expressing human neural stem cells (LMNSC008) demonstrate an inherent tropism to injury sites after intranasal (IN) administration. We hypothesize that IN delivered LMNSC008 cells migrate to primary and secondary injury sites and modulate biomarkers associated with neuroprotection and tissue regeneration. To test this, immunocompetent adult female rats received a controlled cortical impact injury (CCI) or sham surgery. LMNSC008 cells or a vehicle (VEH) were administered IN on postoperative days 7, 9, 11, 13, 15, and 17. The distribution and migration of eGFP-expressing LMNSC008 cells were quantified over 1 mm-thick optically cleared (CLARITY) coronal brain sections from TBI and SHAM controls. NSC migration was observed along white matter tracts projecting toward the hippocampus and regions of TBI. ELISA and Nanostring assays revealed a shift in tissue gene expression in LMNSC008 treated rats relative to controls. LMNSC008 treatment reduced expression of genes and pathways involved in inflammatory response, microglial function, and various cytokines and receptors. The data demonstrate a robust proof-of-concept for LMNSC008 therapy for TBI and provides a strong rationale for IN delivery for translation in TBI patients.

Sustained attention performance deficits in the three-choice serial reaction time task in male and female rats after experimental brain trauma.

Impaired attention is central to the cognitive deficits associated with long-term sequelae for many traumatic brain injury (TBI) survivors. Assessing complex sustained attention post-TBI is clinically-relevant and may provide reliable avenues towards developing therapeutic and rehabilitation targets in both males and females. We hypothesized that rats subjected to a moderate TBI will exhibit attentional deficits seen as reduced accuracy and increased distractibility in an operant 3-choice serial reaction time task (3-CSRT), designed as an analogue of the clinical continuous performance test. Upon reaching baseline of 70% accuracy at the 300 ms cue, adult male and female Sprague-Dawley rats were subjected to a controlled cortical impact (2.8 mm deformation at 4 m/s) or sham injury over the right parietal cortex. After two weeks of recovery, they were retested on the 3-CSRT for ten days. Dependent measures include percent accuracy (overall and for each of the three cue ports), percent omissions, as well as latency to instrumental poke and retrieve reward. Results demonstrate that both males and females displayed reduced percent accuracy and increased omissions when re-tested post-TBI on 3-CSRT compared to Sham rats and to their own pre-insult baseline (p's < 0.05). Performance accuracy was impaired consistently throughout the ten days of post-surgery re-testing, suggesting pronounced and long-lasting dysfunction in sustained attention processes. Deficits were specifically more pronounced when the cue was pseudorandomly presented in the left-side cue port (p < 0.05), mirroring clinical hemispatial neglect. These data demonstrate significant and persistent complex attention impairments in both sexes after TBI, rendering identifying efficient therapies for cognitive recovery as pivotal.

Enriching adult male rats prior to traumatic brain injury does not attenuate neurobehavioral or histological deficits.

Environmental enrichment (EE) confers significant increases in neurobehavioral and cognitive recovery and decreases histological damage in various models of traumatic brain injury (TBI). However, despite EE's pervasiveness, little is known regarding its prophylactic potential. Thus, the goal of the current study was to determine whether enriching rats prior to a controlled cortical impact exerts protection as evidenced by attenuated injury-induced neurobehavioral and histological deficits relative to rats without prior EE. The hypothesis was that enrichment prior to TBI would be protective. After two weeks of EE or standard (STD) housing, anesthetized adult male rats received either a controlled cortical impact (2.8 mm deformation at 4 m/s) or sham injury and then were placed in EE or STD conditions. Motor (beam-walk) and cognitive (spatial learning) performance were assessed on post-operative days 1-5 and 14-18, respectively. Cortical lesion volume was quantified on day 21. The group that was housed in STD conditions before TBI and received post-injury EE performed significantly better in motor, cognitive, and histological outcomes vs. both groups in STD conditions regardless of whether having received pre-injury EE or not (p < 0.05). That no differences in any endpoint were revealed between the two STD-housed groups after TBI suggests that enriching rats prior to TBI does not attenuate neurobehavioral or histological deficits and therefore does not support the hypothesis.

Milnacipran Ameliorates Executive Function Impairments following Frontal Lobe Traumatic Brain Injury in Male Rats: A Multimodal Behavioral Assessment.

Traumatic brain injuries (TBIs) affect more than 10 million patients annually worldwide, causing long-term cognitive and psychosocial impairments. Frontal lobe TBIs commonly impair executive function, but laboratory models typically focus primarily on spatial learning and declarative memory. We implemented a multi-modal approach for clinically relevant cognitive-behavioral assessments of frontal lobe function in rats with TBI and assessed treatment benefits of the serotonin-norepinephrine reuptake inhibitor, milnacipran (MLN). Two attentional set-shifting tasks (AST) evaluated cognitive flexibility via the rats' ability to locate food-based rewards by learning, unlearning, and relearning sequential rule sets with shifting salient cues. Adult male rats reached stable pre-injury operant AST (oAST) performance in 3-4 weeks, then were isoflurane-anesthetized, subjected to a unilateral frontal lobe controlled cortical impact (2.4 mm depth, 4 m/sec velocity) or Sham injury, and randomized to treatment conditions. Milnacipran (30 mg/kg/day) or vehicle (VEH; 10% ethanol in saline) was administered intraperitoneally via implanted osmotic minipumps (continuous infusions post-surgery, 60 µL/h). Rats had a 10-day recovery post-TBI/Sham before performing light/location-based oAST for 10 days and, subsequently, odor/media-based digging AST (dAST) on the last test day (26-27 days post-injury) before sacrifice. Both AST tests revealed significant deficits in TBI+VEH rats, seen as elevated total trials and errors (p < 0.05), which generally normalized in MLN-treated rats (p < 0.05). This first simultaneous dual AST assessment demonstrates oAST and dAST are sufficiently sensitive and robust to detect subtle attentional and cognitive flexibility executive impairments after frontal lobe TBI in rats. Chronic MLN administration shows promise for attenuation of post-TBI executive function deficits, thus meriting further investigation.

Environmental enrichment improves traumatic brain injury-induced behavioral phenotype and associated neurodegenerative process.

Traumatic brain injury (TBI) causes persistent cognitive impairment and neurodegeneration. Environmental enrichment (EE) refers to a housing condition that promotes sensory and social stimulation and improves cognition and motor performance but the underlying mechanisms responsible for such beneficial effects are not well defined. In this study, anesthetized adult rats received either a moderate-to-severe controlled cortical impact (CCI) or sham surgery and then were housed in either EE or standard conditions. The results showed a significant increase in protein nitration and oxidation of lipids, impaired cognition and motor performance, and augmented N-methyl-d-aspartate receptor subtype-1 (NMDAR1) levels. However, EE initiated 24 h after CCI resulted in reduced oxidative insult and microglial activation and significant improvement in beam-balance/walk performance and both spatial learning and memory. We hypothesize that following TBI there is an upstream activation of NMDAR that promotes oxidative insult and an inflammatory response, thereby resulting in impaired behavioral functioning but EE may exert a neuroprotective effect via sustained downregulation of NMDAR1.

Resuscitation with epinephrine worsens cerebral capillary no-reflow after experimental pediatric cardiac arrest: An in vivo multiphoton microscopy evaluation.

Epinephrine is the principal resuscitation therapy for pediatric cardiac arrest (CA). Clinical data suggest that although epinephrine increases the rate of resuscitation, it fails to improve neurological outcome, possibly secondary to reductions in microvascular flow. We characterized the effect of epinephrine vs. placebo administered at resuscitation from pediatric asphyxial CA on microvascular and macrovascular cortical perfusion assessed using in vivo multiphoton microscopy and laser speckle flowmetry, respectively, and on brain tissue oxygenation (PbO2), behavioral outcomes, and neuropathology in 16-18-day-old rats. Epinephrine-treated rats had a more rapid return of spontaneous circulation and brisk immediate cortical reperfusion during 1-3 min post-CA vs. placebo. However, at the microvascular level, epinephrine-treated rats had penetrating arteriole constriction and increases in both capillary stalling (no-reflow) and cortical capillary transit time 30-60 min post-CA vs. placebo. Placebo-treated rats had increased capillary diameters post-CA. The cortex was hypoxic post-CA in both groups. Epinephrine treatment worsened reference memory performance vs. shams. Hippocampal neuron counts did not differ between groups. Resuscitation with epinephrine enhanced immediate reperfusion but produced microvascular alterations during the first hour post-resuscitation, characterized by vasoconstriction, capillary stasis, prolonged cortical transit time, and absence of compensatory cortical vasodilation. Targeted therapies mitigating the deleterious microvascular effects of epinephrine are needed.

Chronic unpredictable stress during adolescence protects against adult traumatic brain injury-induced affective and cognitive deficits.

Pre-clinical early-life stress paradigms model early adverse events in humans. However, the long-term behavioral consequences of early-life adversities after traumatic brain injury (TBI) in adults have not been examined. In addition, endocannabinoids may protect against TBI neuropathology. Hence, the current study assessed the effects of adverse stress during adolescence on emotional and cognitive performance in rats sustaining a TBI as adults, and how cannabinoid receptor 1 (CB1) activation impacts the outcome. On postnatal days (PND) 30-60, adolescent male rats were exposed to four weeks of chronic unpredictable stress (CUS), followed by four weeks of no stress (PND 60-90), or no stress at any time (Control), and then anesthetized and provided a cortical impact of moderate severity (2.8 mm tissue deformation at 4 m/s) or sham injury. TBI and Sham rats (CUS and Control) were administered either arachidonyl-2'-chloroethylamide (ACEA; 1 mg/kg, i.p.), a CB1 receptor agonist, or vehicle (VEH; 1 mL/kg, i.p.) immediately after surgery and once daily for 7 days. Anxiety-like behavior was assessed in an open field test (OFT) and learning and memory in novel object recognition (NOR) and Morris water maze (MWM) tasks. No differences were revealed among the Sham groups in any behavioral assessment and thus the groups were pooled. In the ACEA and VEH-treated TBI groups, CUS increased exploration in the OFT, enhanced NOR focus, and decreased the time to reach the escape platform in the MWM, suggesting decreased anxiety and enhanced learning and memory relative to the Control group receiving VEH (p < 0.05). ACEA also enhanced NOR and MWM performance in the Control + TBI group (p < 0.05). These data suggest that 4 weeks of CUS provided during adolescence may provide protection against TBI acquired during adulthood and/or induce adaptive behavioral responses. Moreover, CB1 receptor agonism produces benefits after TBI independent of CUS protection.

Intranasally Administered L-Myc-Immortalized Human Neural Stem Cells Migrate to Primary and Distal Sites of Damage after Cortical Impact and Enhance Spatial Learning.

As the success of stem cell-based therapies is contingent on efficient cell delivery to damaged areas, neural stem cells (NSCs) have promising therapeutic potential because they inherently migrate to sites of central nervous system (CNS) damage. To explore the possibility of NSC-based therapy after traumatic brain injury (TBI), isoflurane-anesthetized adult male rats received a controlled cortical impact (CCI) of moderate severity (2.8 mm deformation at 4 m/s) or sham injury (i.e., no cortical impact). Beginning 1-week post-injury, the rats were immunosuppressed and 1 × 106 human NSCs (LM-NS008.GFP.fLuc) or vehicle (VEH) (2% human serum albumen) were administered intranasally (IN) on post-operative days 7, 9, 11, 13, 15, and 17. To evaluate the spatial distributions of the LM-NSC008 cells, half of the rats were euthanized on day 25, one day after completion of the cognitive task, and the other half were euthanized on day 46. 1 mm thick brain sections were optically cleared (CLARITY), and volumes were imaged by confocal microscopy. In addition, LM-NSC008 cell migration to the TBI site by immunohistochemistry for human-specific Nestin was observed at day 39. Acquisition of spatial learning was assessed in a well-established Morris water maze task on six successive days beginning on post-injury day 18. IN administration of LM-NSC008 cells after TBI (TBI + NSC) significantly facilitated spatial learning relative to TBI + VEH rats (p < 0.05) and had no effect on sham + NSC rats. Overall, these data indicate that IN-administered LM-NSC008 cells migrate to sites of TBI damage and that their presence correlates with cognitive improvement. Future studies will expand on these preliminary findings by evaluating other LM-NSC008 cell dosing paradigms and evaluating mechanisms by which LM-NSC008 cells contribute to cognitive recovery.

A combined therapeutic regimen of citalopram and environmental enrichment ameliorates attentional set-shifting performance after brain trauma.

Traumatic brain injuries (TBI) have led to lasting deficits for an estimated 5.3 million American patients. Effective therapies for these patients remain scarce and each of the clinical trials stemming from success in experimental models has failed. We believe that the failures may be, in part, due to the lack of preclinical assessment of cognitive domains that widely affect clinical TBI. Specifically, the behavioral tasks in the TBI literature often do not focus on common executive impairments related to the frontal lobe such as cognitive flexibility. In previous work, we have demonstrated that the attentional set-shifting test (AST), a task analogous to the clinically-employed Wisconsin Card Sorting Test (WCST), could be used to identify cognitive flexibility impairments following controlled cortical impact (CCI) injury. In this study, we hypothesized that both the administration of the antidepressant drug citalopram (CIT) and exposure to a preclinical model of neurorehabilitation, environmental enrichment (EE), would attenuate cognitive performance deficits on AST when provided alone and lead to greater benefits when administered in combination. Adult male rats were subjected to a moderate-severe CCI or sham injury. Rats were randomly divided into experimental groups that included surgical injury, drug therapy, and housing condition. We observed that both CIT and EE provided significant cognitive recovery when administered alone and reversal learning performance recovery increased the most when the therapies were combined (p < 0.05). Ongoing studies continue to evaluate novel ways of assessing more clinically relevant measurements of high order cognitive TBI-related impairments in the rat model.

Preclinical neurorehabilitation with environmental enrichment confers cognitive and histological benefits in a model of pediatric asphyxial cardiac arrest.

Pediatric asphyxial cardiac arrest (ACA) often leaves children with physical, cognitive, and emotional disabilities that affect overall quality of life, yet rehabilitation is neither routinely nor systematically provided. Environmental enrichment (EE) is considered a preclinical model of neurorehabilitation and thus we sought to investigate its efficacy in our established model of pediatric ACA. Male Sprague-Dawley rat pups (post-natal day 16-18) were randomly assigned to ACA (9.5 min) or Sham injury. After resuscitation, the rats were assigned to 21 days of EE or standard (STD) housing during which time motor, cognitive, and anxiety-like (i.e., affective) outcomes were assessed. Hippocampal CA1 cells were quantified on post-operative day-22. Both ACA + STD and ACA + EE performed worse on beam-balance vs. Sham controls (p < 0.05) and did not differ from one another overall (p > 0.05); however, a single day analysis on the last day of testing revealed that the ACA + EE group performed better than the ACA + STD group (p < 0.05) and did not differ from the Sham controls (p > 0.05). Both Sham groups performed better than ACA + STD (p < 0.05) but did not differ from ACA + EE (p > 0.05) in the open field test. Spatial learning and declarative memory were improved and CA1 neuronal loss was attenuated in the ACA + EE vs. ACA + STD group (p < 0.05). Collectively, the data suggest that providing rehabilitation after pediatric ACA can reduce histopathology and improve motor and cognitive ability.

Early Life Stress Preceding Mild Pediatric Traumatic Brain Injury Increases Neuroinflammation but Does Not Exacerbate Impairment of Cognitive Flexibility during Adolescence.

Early life stress (ELS) followed by pediatric mild traumatic brain injury (mTBI) negatively impacts spatial learning and memory and increases microglial activation in adolescent rats, but whether the same paradigm negatively affects higher order executive function is not known. Hence, we utilized the attentional set-shifting test (AST) to evaluate executive function (cognitive flexibility) and to determine its relationship with neuroinflammation and hypothalamic-pituitary-adrenal (HPA) axis activity after pediatric mTBI in male rats. ELS was induced via maternal separation for 180 min per day (MS180) during the first 21 post-natal (P) days, while controls (CONT) were undisturbed. At P21, fully anesthetized rats received a mild controlled cortical impact (2.2 mm tissue deformation at 4 m/sec) or sham injury. AST was evaluated during adolescence on P35-P40 and cytokine expression and HPA activity were analyzed on P42. The data indicate that pediatric mTBI produced a significant reversal learning deficit on the AST versus sham (p < 0.05), but that the impairment was not exacerbated further by MS180. Additionally, ELS produced an overall elevation in set-loss errors on the AST, and increased hippocampal interleukin (IL)-1ß expression after TBI. A significant correlation was observed in executive dysfunction and IL-1ß expression in the ipsilateral pre-frontal cortex and hippocampus. Although the combination of ELS and pediatric mTBI did not worsen executive function beyond that of mTBI alone (p > 0.05), it did result in increased hippocampal neuroinflammation relative to mTBI (p < 0.05). These findings provide important insight into the susceptibility to incur alterations in cognitive and neuroimmune functioning after stress exposure and TBI during early life.

Disruption of basal forebrain cholinergic neurons after traumatic brain injury does not compromise environmental enrichment-mediated cognitive benefits.

Environmental enrichment (EE) attenuates traumatic brain injury (TBI)-induced loss of medial septal (MS) choline acetyltransferase (ChAT)-cells and enhances spatial learning and memory vs. standard (STD) housing. Whether basal forebrain cholinergic neurons (BFCNs) are important mediators of EE-induced benefits after TBI requires further investigation. Anesthetized female rats were randomly assigned to intraseptal infusions of the immunotoxin 192-IgG-saporin (SAP; 0.22 µg in 1.0 µL) or vehicle (VEH; 1.0 µL IgG) followed immediately by a cortical impact (2.8 mm deformation depth at 4 m/s) or sham injury and divided into EE and STD housing. Spatial learning and memory retention were assessed on post-operative days 14-19. MS ChAT+ cells were quantified at 3 weeks. SAP significantly reduced ChAT+ cells in both the EE and STD groups. Cognitive performance was improved in the EE groups, regardless of VEH or SAP infusion, vs. the STD-housed groups (p's < 0.05). No cognitive differences were revealed between the TBI + EE + SAP and TBI + EE + VEH groups (p > 0.05) or between the TBI + STD + SAP and TBI + STD + VEH groups (p > 0.05). These data show that despite significant MS ChAT+ cell loss, the EE-mediated benefit in cognitive recovery is not compromised.

Early life stress increases vulnerability to the sequelae of pediatric mild traumatic brain injury.

Early life stress (ELS) is a risk factor for many psychopathologies that happen later in life. Although stress can occur in cases of child abuse, studies on non-accidental brain injuries in pediatric populations do not consider the possible increase in vulnerability caused by ELS. Hence, we sought to determine whether ELS increases the effects of pediatric mild traumatic brain injury (mTBI) on cognition, hippocampal inflammation, and plasticity. Male rats were subjected to maternal separation for 180 min per day (MS180) or used as controls (CONT) during the first 21 post-natal (P) days. At P21 the rats were anesthetized with isoflurane and subjected to a mild controlled cortical impact or sham injury. At P32 the rats were injected with the cell proliferation marker bromodeoxyuridine (BrdU, 500 mg/kg), then evaluated for spatial learning and memory in a water maze (P35-40) and sacrificed for quantification of Ki67+, BrdU+ and Iba1+ (P42). Neither MS180 nor mTBI impacted cognitive outcome when provided alone but their combination (MS180 + mTBI) decreased spatial learning and memory relative to Sham controls (p < .01). mTBI increased microglial activation and affected BrdU+ cell survival in the ipsilateral hippocampus without affecting proliferation rates. However, only MS180 + mTBI increased microglial activation in the area adjacent to the injury and the contralateral CA1 hippocampal subfield, and decreased cell proliferation in the ipsilateral neurogenic niche. Overall, the data show that ELS increases the vulnerability to the sequelae of pediatric mTBI and may be mediated by increased neuroinflammation.

Paths to Successful Translation of New Therapies for Severe Traumatic Brain Injury in the Golden Age of Traumatic Brain Injury Research: A Pittsburgh Vision.

New neuroprotective therapies for severe traumatic brain injury (TBI) have not translated from pre-clinical to clinical success. Numerous explanations have been suggested in both the pre-clinical and clinical arenas. Coverage of TBI in the lay press has reinvigorated interest, creating a golden age of TBI research with innovative strategies to circumvent roadblocks. We discuss the need for more robust therapies. We present concepts for traditional and novel approaches to defining therapeutic targets. We review lessons learned from the ongoing work of the pre-clinical drug and biomarker screening consortium Operation Brain Trauma Therapy and suggest ways to further enhance pre-clinical consortia. Biomarkers have emerged that empower choice and assessment of target engagement by candidate therapies. Drug combinations may be needed, and it may require moving beyond conventional drug therapies. Precision medicine may also link the right therapy to the right patient, including new approaches to TBI classification beyond the Glasgow Coma Scale or anatomical phenotyping-incorporating new genetic and physiologic approaches. Therapeutic breakthroughs may also come from alternative approaches in clinical investigation (comparative effectiveness, adaptive trial design, use of the electronic medical record, and big data). The full continuum of care must also be represented in translational studies, given the important clinical role of pre-hospital events, extracerebral insults in the intensive care unit, and rehabilitation. TBI research from concussion to coma can cross-pollinate and further advancement of new therapies. Misconceptions can stifle/misdirect TBI research and deserve special attention. Finally, we synthesize an approach to deliver therapeutic breakthroughs in this golden age of TBI research.

Environmental enrichment and amantadine confer individual but nonadditive enhancements in motor and spatial learning after controlled cortical impact injury.

Environmental enrichment (EE) and amantadine (AMT) enhance motor and cognitive outcome after experimental traumatic brain injury (TBI). However, there are no data on the effects of combining these two therapies. Hence, the aim of the current study was to combine EE and AMT after TBI to determine if their net effect further enhances motor and cognitive performance. Anesthetized adult male rats received either a cortical impact of moderate severity or sham injury and then were randomly assigned to EE or standard (STD) housing and once daily administration of AMT (20 mg/kg; i.p.) or saline vehicle (VEH, 1 mL/kg; i.p.) beginning 24 h after injury for 19 days. Motor and cognitive function were assessed on post-surgical days 1-5 and 14-19, respectively. Cortical lesion volume was quantified on day 21. There were no statistical differences among the sham groups regardless of therapy, so the data were pooled. EE, AMT, and their combination (EE + AMT) improved beam-balance, but only EE and EE + AMT enhanced beam-walking. All three treatment paradigms improved spatial learning and memory relative to the VEH-treated STD controls (p < 0.05). No differences were revealed between the EE groups, regardless of treatment, but both were better than the AMT-treated STD group on beam-walking and spatial learning (p < 0.05). Both EE groups equally reduced cortical lesion volume relative to the STD-housed AMT and VEH groups (p < 0.05). The results indicate that although beneficial on their own, EE + AMT do not provide additional benefits after TBI. It is important to note that the lack of additive effects using the current treatment and behavioral protocols does not detract from the benefits of each individual therapy. The findings provide insight for future combination studies.