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.

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.

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.

Chronic treatment with galantamine rescues reversal learning in an attentional set-shifting test after experimental brain trauma.

Approximately 10 million new cases of traumatic brain injury (TBI) are reported each year worldwide with many of these injuries resulting in higher order cognitive impairments. Galantamine (GAL), an acetylcholine esterase inhibitor (AChEI) and positive allosteric modulator of nicotinic acetylcholine receptors (nAChRs), has been reported to ameliorate cognitive deficits after clinical TBI. Previously, we demonstrated that controlled cortical impact (CCI) injury to rats resulted in significant executive function impairments as measured by the attentional set-shifting test (AST), a complex cognitive task analogous to the Wisconsin Card Sorting Test (WCST). We hypothesized that chronic administration of GAL would normalize performance on the AST post-TBI. Isoflurane-anesthetized adult male rats were subjected to moderate CCI (2.8 mm tissue deformation at 4 m/s) or sham injury. Rats were then randomized into one of three treatment groups (i.e., 1 mg/kg GAL, 2 mg/kg GAL, or 1 mL/kg saline vehicle; VEH) or their respective sham controls. GAL or VEH was administered intraperitoneally daily commencing 24 hours post-surgery and until AST testing at 4 weeks post-injury. The AST data revealed significant impairments in the first reversal stage after TBI, seen as increased trials to reach criterion and elevated total errors (p < 0.05). These behavioral flexibility deficits were equally normalized by the administration of both doses of GAL (p < 0.05). Additionally, the higher dose of GAL (2 mg/kg) also significantly reduced cortical lesion volume compared to TBI + VEH controls (p < 0.05). In summary, daily GAL administration provides an efficacious treatment for cognitive deficits and histological recovery after experimental brain trauma. Clinically, these findings are promising considering robust results were attained using a pharmacotherapy already used in the clinic to treat mild dementia.

Spontaneous recovery of traumatic brain injury-induced functional deficits is not hindered by daily administration of lorazepam.

Agitation and aggression are common sequelae of traumatic brain injury (TBI) and pose a challenge to physicians and other health providers during acute patient care and subsequent neurorehabilitation. Antipsychotic drugs (APDs) are routinely administered to manage TBI patients displaying such maladaptive behaviors despite several clinical and preclinical studies demonstrating that they hinder recovery. A potentially viable alternative to APDs may be the benzodiazepines, which have differing mechanisms of action. Hence, the aim of the study was to test the hypothesis that lorazepam (LOR) would not impede recovery after TBI. Anesthetized adult male rats received a cortical impact or sham injury and then were intraperitoneally administered LOR (0.1mg/kg, 1.0mg/kg, or 2.0mg/kg) or vehicle (VEH; 1mL/kg) commencing 24-h after surgery and once daily for 19days. Motor and cognitive outcomes were assessed on post-operative days 1-5 and 14-19, respectively. No differences were revealed among the four sham control groups and thus they were pooled into one inclusive SHAM group. The SHAMs performed better than all TBI groups on all assessments (p<0.05). Regarding TBI, the 2.0mg/kg LOR group performed better than the VEH and 0.1mg/kg or 1.0mg/kg LOR groups on every task (p<0.05); no differences were observed among the latter three groups on any endpoint (p>0.05). Overall, these preclinical behavioral data support the hypothesis and reveal a therapeutic benefit with the higher dose of LOR. The findings suggest that LOR may be an alternative, to APDs, for controlling agitation without compromising spontaneous recovery and perhaps could afford a dual benefit by also promoting therapeutic efficacy.

Rehabilitative Success After Brain Trauma by Augmenting a Subtherapeutic Dose of Environmental Enrichment With Galantamine.

BACKGROUND: Environmental enrichment (EE) confers benefits after traumatic brain injury (TBI) when provided daily for > 6 hours, but not 2 or 4 hours, which more accurately reflects the daily amount of clinical rehabilitation. The lack of benefit with sub-therapeutic EE suggests that augmentation with galantamine (GAL), which enhances cognition after TBI, may be indicated to confer benefits. OBJECTIVE: To test the hypothesis that 2 and 4 hours of EE paired with GAL will provide benefits comparable to 24 hours of EE alone. Moreover, all EE groups will perform better than the standard (STD)-housed GAL group. METHODS: Anesthetized rats received a TBI or sham injury and then were randomized to receive intraperitoneal injections of GAL (2 mg/kg) or saline vehicle (VEH; 1 mL/kg) beginning 24 hours after surgery and once daily while receiving EE for 2, 4, or 24 hours. Motor and cognitive assessments were conducted on postoperative days 1-5 and 14-19, respectively. RESULTS: Motor function was significantly improved in the TBI + 24-hour EE group versus the TBI + STD + VEH and TBI + STD + GAL groups ( P < .05). Cognitive performance was enhanced in all EE groups as well as in the TBI + STD + GAL versus TBI + STD + VEH ( P < .05). Moreover, the 2- and 4-hour EE groups receiving GAL did not differ from the 24-hour EE group ( P > .05) and performed better than GAL alone ( P < .05). CONCLUSIONS: The findings support the hypothesis and have clinical relevance because, often, only brief rehabilitation may be available in the clinic and, thus, augmenting with a pharmacotherapy such as GAL may lead to outcomes that are significantly better than either therapy alone.

Galantamine and Environmental Enrichment Enhance Cognitive Recovery after Experimental Traumatic Brain Injury But Do Not Confer Additional Benefits When Combined.

Environmental enrichment (EE) enhances cognition after traumatic brain injury (TBI). Galantamine (GAL) is an acetylcholinesterase inhibitor that also may promote benefits. Hence, the aims of this study were to assess the efficacy of GAL alone (standard [STD] housing) and in combination with EE in adult male rats after TBI. The hypothesis was that both therapies would confer motor, cognitive, and histological benefits when provided singly, but that their combination would be more efficacious. Anesthetized rats received a controlled cortical impact or sham injury, then were randomly assigned to receive GAL (1, 2, or 3 mg/kg; intraperitoneally [i.p.]) or saline vehicle (VEH; 1 mL/kg; i.p.) beginning 24 h after surgery and once daily for 21 days (experiment 1). Motor (beam-balance/walk) and cognitive (Morris water maze [MWM]) assessments were conducted on post-operative Days 1-5 and 14-19, respectively. Cortical lesion volumes were quantified on Day 21. Sham controls were better versus all TBI groups. No differences in motor function or lesion volumes were observed among the TBI groups (p > 0.05). In contrast, GAL (2 mg/kg) enhanced MWM performance versus VEH and GAL (1 and 3 mg/kg; p < 0.05). In experiment 2, GAL (2 mg/kg) or VEH was combined with EE and the data were compared with the STD-housed groups from experiment 1. EE alone enhanced motor performance over the VEH-treated and GAL-treated (2 mg/kg) STD-housed groups (p < 0.05). Moreover, both EE groups (VEH or GAL) facilitated spatial learning and reduced lesion size versus STD + VEH controls (p < 0.05). No additional benefits were observed with the combination paradigm, which does not support the hypothesis. Overall, the data demonstrate that EE and once daily GAL (2 mg/kg) promote cognitive recovery after TBI. Importantly, the combined therapies did not negatively affect outcome and thus this therapeutic protocol may have clinical utility.

Abbreviated environmental enrichment confers neurobehavioral, cognitive, and histological benefits in brain-injured female rats.

Environmental enrichment (EE) promotes behavioral recovery after experimental traumatic brain injury (TBI). However, the chronic rehabilitation provided in the laboratory is not analogous to the clinic where physiotherapy is typically limited. Moreover, females make up approximately 40% of the clinical TBI population, yet they are seldom studied in brain trauma. Hence, the goal of this study was to test the hypothesis that abbreviated EE would confer neurobehavioral, cognitive, and histological benefits in brain injured female rats. Anesthetized rats received a cortical impact of moderate-to-severe injury (2.8mm tissue deformation at 4m/s) or sham surgery and then were randomly assigned to groups receiving standard (STD) housing or 4h, 6h, or 24h of EE daily. Motor function (beam-balance/walk and rotarod) was assessed on post-operative days 1-5 and every other day from 1 to 19, respectively. Spatial learning/memory (Morris water maze) was evaluated on days 14-19, and cortical lesion volume was quantified on day 21. No statistical differences were appreciated among the sham controls in any assessment and thus the data were pooled. All EE conditions improved motor function and memory retention, but only 6h and 24h enhanced spatial learning relative to STD (p<0.05). Moreover, EE, regardless of duration reduced cortical lesion volume (p<0.05). These data confirm that abbreviated EE confers robust neurobehavioral, cognitive, and histological benefits in TBI female rats, which supports the hypothesis and strengthens the utility of EE as a pre-clinical model of neurorehabilitation.

Combination therapies for neurobehavioral and cognitive recovery after experimental traumatic brain injury: Is more better?

Traumatic brain injury (TBI) is a significant health care crisis that affects two million individuals in the United Sates alone and over ten million worldwide each year. While numerous monotherapies have been evaluated and shown to be beneficial at the bench, similar results have not translated to the clinic. One reason for the lack of successful translation may be due to the fact that TBI is a heterogeneous disease that affects multiple mechanisms, thus requiring a therapeutic approach that can act on complementary, rather than single, targets. Hence, the use of combination therapies (i.e., polytherapy) has emerged as a viable approach. Stringent criteria, such as verification of each individual treatment plus the combination, a focus on behavioral outcome, and post-injury vs. pre-injury treatments, were employed to determine which studies were appropriate for review. The selection process resulted in 37 papers that fit the specifications. The review, which is the first to comprehensively assess the effects of combination therapies on behavioral outcomes after TBI, encompasses five broad categories (inflammation, oxidative stress, neurotransmitter dysregulation, neurotrophins, and stem cells, with and without rehabilitative therapies). Overall, the findings suggest that combination therapies can be more beneficial than monotherapies as indicated by 46% of the studies exhibiting an additive or synergistic positive effect versus on 19% reporting a negative interaction. These encouraging findings serve as an impetus for continued combination studies after TBI and ultimately for the development of successful clinically relevant therapies.

A combined therapeutic regimen of buspirone and environmental enrichment is more efficacious than either alone in enhancing spatial learning in brain-injured pediatric rats.

Buspirone, a 5-HT1A receptor agonist, and environmental enrichment (EE) enhance cognition and reduce histopathology after traumatic brain injury (TBI) in adult rats, but have not been fully evaluated after pediatric TBI, which is the leading cause of death in children. Hence, the aims of this study were to assess the efficacy of buspirone alone (Experiment 1) and in combination with EE (Experiment 2) in TBI postnatal day-17 male rats. The hypothesis was that both therapies would confer cognitive and histological benefits when provided singly, but their combination would be more efficacious. Anesthetized rats received a cortical impact or sham injury and then were randomly assigned to receive intraperitoneal injections of buspirone (0.08 mg/kg, 0.1 mg/kg, and 0.3 mg/kg) or saline vehicle (1.0 mL/kg) 24 h after surgery and once daily for 16 days (Experiment 1). Spatial learning and memory were assessed using the Morris water maze (MWM) on post-operative days 11-16, and cortical lesion volume was quantified on day 17. Sham controls for each condition were significantly better than all TBI groups. In the TBI groups, buspirone (0.1 mg/kg) enhanced MWM performance versus vehicle and buspirone (0.08 mg/kg and 0.3 mg/kg) (p<0.05) and reduced lesion volume relative to vehicle (p=0.038). In Experiment 2, buspirone (0.1 mg/kg) or vehicle was combined with EE after TBI, and the data were compared to the standard (STD)-housed groups from Experiment 1. EE lead to a significant enhancement of spatial learning and a reduction in lesion size versus STD. Moreover, the combined treatment group (buspirone+EE) performed markedly better than the buspirone+STD and vehicle+EE groups, which suggests an additive effect and supports the hypothesis. The data replicate previous studies assessing these therapies in adult rats. These novel findings may have important rehabilitation-relevant implications for clinical pediatric TBI.

Traumatic brain injury-induced cognitive and histological deficits are attenuated by delayed and chronic treatment with the 5-HT1A-receptor agonist buspirone.

The aim of this study was to evaluate the potential efficacy of the serotonin(1A) (5-HT(1A)) receptor agonist buspirone (BUS) on behavioral and histological outcome after traumatic brain injury (TBI). Ninety-six isoflurane-anesthetized adult male rats were randomized to receive either a controlled cortical impact or sham injury, and then assigned to six TBI and six sham groups receiving one of five doses of BUS (0.01, 0.05, 0.1, 0.3, or 0.5 mg/kg) or saline vehicle (VEH, 1.0 mL/kg). Treatments began 24 h after surgery and were administered intraperitoneally once daily for 3 weeks. Motor function (beam-balance/beam-walk tests) and spatial learning/memory (Morris water maze) were assessed on post-operative days 1-5 and 14-19, respectively. Morphologically intact CA1/CA3 cells and cortical lesion volume were quantified at 3 weeks. No differences were observed among the BUS and VEH sham groups in any end-point measure and thus the data were pooled. Regarding the TBI groups, repeated-measures ANOVAs revealed that the 0.3 mg/kg dose of BUS enhanced cognitive performance relative to VEH and the other BUS doses (p<0.05), but did not significantly impact motor function. Moreover, the same dose conferred selective histological protection as evidenced by smaller cortical lesions, but not greater CA1/CA3 cell survival. No significant behavioral or histological differences were observed among the other BUS doses versus VEH. These data indicate that BUS has a narrow therapeutic dose response, and that 0.3 mg/kg is optimal for enhancing spatial learning and memory in this model of TBI. BUS may have potential as a novel pharmacotherapy for clinical TBI.

Chronic administration of antipsychotics impede behavioral recovery after experimental traumatic brain injury.

Antipsychotics are often administered to traumatic brain injured (TBI) patients as a means of controlling agitation, albeit the rehabilitative consequences of this intervention are not well known. Hence, the goal of this study was to evaluate the effects of risperidone (RISP) and haloperidol (HAL) on behavioral outcome after experimental TBI. Anesthetized rats received either a cortical impact or sham injury and then were randomly assigned to five TBI (RISP 0.045mg/kg, RISP 0.45mg/kg, RISP 4.5mg/kg, HAL 0.5mg/kg and VEHicle 1mL/kg) and three Sham (RISP 4.5mg/kg, HAL 0.5mg/kg and VEH 1mL/kg) groups. Treatments began 24h after surgery and were provided once daily for 19 days. Behavior was assessed with established motor (beam-balance/walk) and cognitive (spatial learning/memory in a water maze) tasks on post-operative days 1-5 and 14-19, respectively. RISP and HAL delayed motor recovery, impaired the acquisition of spatial learning, and slowed swim speed relative to VEH in both TBI and sham groups. These data indicate that chronic administration of RISP and HAL impede behavioral recovery after TBI and impair performance in uninjured controls.

Administration of haloperidol and risperidone after neurobehavioral testing hinders the recovery of traumatic brain injury-induced deficits.

AIMS: Agitation and aggression are common behavioral sequelae of traumatic brain injury (TBI). The management of these symptoms is critical for effective patient care and therefore antipsychotics are routinely administered even though the benefits vs. risks of this approach on functional outcome after TBI are unclear. A recent study from our group revealed that both haloperidol and risperidone impaired recovery when administered prior to testing. However, the results may have been confounded by drug-induced sedation. Hence, the current study reevaluated the behavioral effects of haloperidol and risperidone when provided after daily testing, thus circumventing the potential sedative effect. MAIN METHODS: Fifty-four isoflurane-anesthetized male rats received a cortical impact or sham injury and then were randomly assigned to three TBI and three sham groups that received haloperidol (0.5 mg/kg), risperidone (0.45 mg/kg), or vehicle (1.0 mL/kg). Treatments began 24 h after surgery and were administered (i.p.) every day thereafter for 19 days. Motor and cognitive function was assessed on post-operative days 1-5 and 14-19, respectively. Hippocampal CA(1)/CA(3) neurons and cortical lesion volume were quantified at 3 weeks. KEY FINDINGS: Only risperidone delayed motor recovery, but both antipsychotics impaired spatial learning relative to vehicle (p<0.05). Neither swim speed nor histological outcomes were affected. No differences were observed between the haloperidol and risperidone groups in any task. SIGNIFICANCE: These data support our previous finding that chronic haloperidol and risperidone hinder the recovery of TBI-induced deficits, and augment those data by demonstrating that the effects are not mediated by drug-induced sedation.

Environmental enrichment-mediated functional improvement after experimental traumatic brain injury is contingent on task-specific neurobehavioral experience.

Environmental enrichment (EE) is superior to standard (STD) housing in promoting functional recovery after traumatic brain injury (TBI). However, whether the EE-mediated benefits after TBI are dependent on exposure to enrichment during neurobehavioral training has not been elucidated. To address this issue, isoflurane-anesthetized adult male rats received either a cortical impact or sham injury and were then randomly assigned to early EE, delayed EE, continuous EE or no EE (i.e., STD conditions). Continuous EE or no EE was initiated immediately after surgery and continued for the duration of the study. Early EE began directly after surgery, continued for 1 week, and was then followed by STD living (2 rats per cage) for the remainder of the study, while delayed EE commenced 1 week after early STD housing. Functional outcome was assessed with established motor and cognitive tests on post-injury days 1-5 and 14-18, respectively. CA(1)/CA(3) neurons were quantified at 3 weeks. CA(3) cell loss was significantly attenuated in the TBI+continuous EE group versus the TBI+no EE group. Beam-walking was facilitated in the TBI groups that received either early or continuous EE versus those receiving delayed or no EE. Cognitive training was enhanced in the TBI groups that received continuous or delayed EE versus the early EE or no EE groups. These data suggest that EE-mediated functional improvement after TBI is contingent on task-specific neurobehavioral experience.