Several studies have shown that housing rats in an enriched environment (EE) after traumatic brain injury (TBI) improves functional and histological outcome. The typical EE includes exploratory, sensory, and social components in cages that are often vastly larger than standard (STD) housing. It is uncertain, however, whether a single or specific component is sufficient to confer these benefits after TBI, or if all, perhaps in an additive or synergistic manner, are necessary. To clarify this ambiguity, anesthetized adult male rats were subjected to either a controlled cortical impact or sham injury, and then were randomly assigned to five different housing paradigms: (1) EE (typical), (2) EE (-social), (3) EE (-stimuli), (4) STD (typical), and (5) STD (+stimuli). Motor and cognitive function were assessed using conventional motor (beam-balance/traversal) and cognitive (spatial learning in a Morris water maze) tests on postoperative days 1-5 and 14-19, respectively, and cortical lesion volume and CA1/CA3 cell loss were quantified at 3 weeks. No significant differences were observed among the sham groups in any comparison and thus their data were pooled (i.e., SHAM). In the TBI groups, typical EE improved beam-balance versus both STD (+stimuli) and EE (-social), it facilitated the acquisition of spatial learning and memory retention versus all other housing conditions (p < 0.003), and it reduced lesion volume and CA3 cell loss versus STD (typical) housing. While rats in the three atypical EE conditions exhibited slightly better cognitive performance and histological protection versus the typical STD group, the overall effects were not significant. These data suggest that exposing TBI rats to any of the three components individually may be more advantageous than no enrichment, but only exposure to typical EE yields optimal benefits.

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.

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 hrs 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.Key findings-Hippocampal CA 1 /CA 3 neurons and cortical lesion volume were quantified at 3 weeks. 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. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. 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. NIH Public Access

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 0.045 mg/kg, RISP 0.45 mg/kg, RISP 4.5 mg/kg, HAL 0.5 mg/kg, VEHicle 1 mL/kg) and three Sham (RISP 4.5 mg/kg, HAL 0.5 mg/kg, VEH 1 mL/kg) groups. Treatments began 24 hrs after surgery and were provided once daily for 19 days. Behavior was assessed with established motor (beambalance/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.