Acute treatment with the 5-HT 1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) or chronic environmental enrichment (EE) hasten behavioral recovery after experimental traumatic brain injury (TBI). The aim of this study was to determine if combining these interventions would confer additional benefit. Anesthetized adult male rats received either a cortical impact or sham injury followed 15 min later by a single intraperitoneal injection of 8-OH-DPAT (0.5 mg/kg) or saline vehicle (1.0 mL/kg) and then randomly assigned to either enriched or standard (STD) housing. Behavioral assessments were conducted utilizing established motor and cognitive tests on post-injury days 1-5 and 14-18, respectively. Hippocampal CA 1 /CA 3 neurons were quantified at 3 weeks. Both 8-OH-DPAT and EE attenuated CA 3 cell loss. 8-OH-DPAT enhanced spatial learning in a Morris water maze (MWM) as revealed by differences between the TBI+8-OH-DPAT+STD and TBI+VEHICLE+STD groups (P=0.0014). EE improved motor function as demonstrated by reduced time to traverse an elevated narrow beam in both the TBI+8-OH-DPAT+EE and TBI+VEHICLE +EE groups vs. the TBI+VEHICLE+STD group (P=0.0007 and P=0.0016, respectively). EE also facilitated MWM learning as evidenced by both the TBI+8-OH-DPAT+EE and TBI+VEHICLE+EE groups locating the escape platform quicker than the TBI+VEHICLE+STD group (P's<0.0001). MWM differences were also observed between the TBI+8-OH-DPAT+EE and TBI+8-OH-DPAT +STD groups (P=0.0004) suggesting that EE enhanced the effect of 8-OH-DPAT. However, there was no difference between the TBI+8-OH-DPAT+EE and TBI+VEHICLE+EE groups. These data replicate previous results from our laboratory showing that both a single systemic administration of 8-OH-DPAT and EE improve recovery after TBI and extend those findings by elucidating that the combination of treatments in this particular paradigm did not confer additional benefit. One explanation for the lack of an additive effect is that EE is a very effective treatment and thus there is very little room for 8-OH-DPAT to confer additional statistically significant improvement.

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.

A powerful convergence of genetics, neuroimaging and epidemiological research has identified biological pathways mediating individual differences in complex behavioral processes and related risk for disease. Orthologous genetic variation in non-human primates represents a unique opportunity to characterize the detailed molecular and cellular mechanisms which bias behaviorally- and clinically-relevant brain function. We report that a rhesus macaque orthologue of a common polymorphism of the serotonin transporter gene (rh5-HTTLPR) has strikingly similar effects on behavior and brain morphology to those in humans. Specifically, the rh5-HTTLPR Short allele broadly impacts cognitive choice behavior and brain morphology without observably affecting 5-HT transporter or 5-HT1A concentrations in vivo. Collectively, our findings indicate that 5-HTTLPR-associated behavioral effects reflect genotype-dependent biases in cortical development rather than static differences in serotonergic signaling mechanisms. Moreover, these data highlight the vast potential of non-human primate models in advancing our understanding of human genetic variation impacting behavior and neuropsychiatric disease liability.

Cocaine users display a wide range of cognitive impairments. Because treatment outcome is dependent on baseline cognitive ability, it is clinically important to understand the underlying neurobiology of these deficits. Therefore, it is crucial to determine whether cocaine exposure by itself is an etiological factor, and if so, to determine the overall nature of cognitive deficits associated with cocaine use. This will help to guide therapeutic approaches that address cognitive components of cocaine use in order to improve treatment outcome. We used rhesus monkeys in a longitudinal study in which 14 animals were characterized prior to assignment to matched control (n=6) and cocaine self-administration (n=8) groups. Self-administration took place on four consecutive days/week over nine months, with a maximum (and typical) daily cumulative intake of 3.0 mg/kg. Weekly cognitive assessments (total of 36) were conducted following a 72 hour drug free period. We employed a stimulus discrimination task with reversal to evaluate associative learning and the cognitive control/flexibility needed to adapt to changes in reward contingencies. Following extended self-administration, initial accuracy on the stimulus discrimination indicated intact associative learning. However, animals were impaired at maintaining high levels of accuracy needed to reach criterion and initiate the reversal. Increasing the reward contrast between stimuli permitted evaluation of reversal performance, and revealed striking deficits in the cocaine group. Impairments in visual working memory were also observed using a delayed-match-to-sample task. These results suggest a combination of generalized, possibly attentional, impairments, along with a more specific cognitive control impairment implicating orbitofrontal cortex dysfunction.

Environmental enrichment (EE) and serotonin 1A (5-HT 1A )-receptor agonists provide significant benefit after experimental traumatic brain injury (TBI). The aim of this study was to test the hypothesis that combining these therapies would produce an effect that is more robust than either therapy alone. Anesthetized adult male rats received a cortical impact or sham injury and then were randomly assigned to EE or standard (STD) housing where they received either buspirone (0.3 mg/kg) or vehicle (1.0 mL/kg) once daily for 3 weeks. Motor and cognitive assessments were conducted on post-injury days 1-5 and 14-19, respectively. CA1/3 neurons were quantified at 3 weeks. No differences were observed among buspirone and vehicle sham groups in any task regardless of housing condition and thus the data were pooled. CA3 cell loss was reduced in the TBI + EE + buspirone and TBI + EE + vehicle groups. Motor recovery, spatial learning, and memory retention were enhanced in the TBI + EE + buspirone, TBI + EE + vehicle, and TBI + STD + buspirone groups versus the TBI + STD + vehicle group ( p £ 0.005). Moreover, spatial learning was significantly better in the TBI + EE + buspirone group versus the TBI + STD + buspirone group ( p < 0.0001). No differences were revealed between the buspirone and vehicle EE groups. These data show that EE and buspirone benefit functional outcome after TBI, but their combination is not more robust than either alone, which does not support the hypothesis. The lack of an additive effect may be due to the early-and-continuous EE paradigm on its own producing marked benefits, resulting in a ceiling effect. The evaluation of buspirone in a delayed-and-abbreviated EE paradigm is ongoing in our laboratory.

It is well established that a relatively brief exposure to environmental enrichment (EE) enhances motor and cognitive performance after experimental traumatic brain injury (TBI), but it is not known whether the benefits can be sustained after EE is discontinued. To address this important rehabilitation-relevant concern, anesthetized rats received a controlled cortical impact (CCI) or sham injury, and for phase 1 of the experiment were randomly assigned to either 3 weeks of EE or standard (STD) housing. Neurobehavioral outcome was assessed by established motor and cognitive tests on postoperative days 1-5 and 14-18, respectively. Beam-balance and spatial learning were facilitated in the TBI + EE more than the TBI + STD group ( p < 0.0001). In phase 2 of the experiment, half of the rats in EE were transferred to STD conditions (TBI + EE + STD and sham + EE + STD), and neurobehavior was re-assessed once per month for 6 months. The TBI + EE and TBI + EE + STD groups performed markedly better in the water maze than the TBI + STD group ( p < 0.0001), and did not differ from one another ( p = 0.53). These data replicate those of several studies from our laboratory showing that EE enhances recovery after CCI injury, and extend those findings by demonstrating that the cognitive benefits are maintained for at least 6 months post-rehabilitation. The persistent benefits shown with this paradigm provide further support for EE as a pre-clinical model of rehabilitation that can be further explored, either alone or in combination with pharmacotherapies, for optimal neurorehabilitation after TBI.

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 isofluraneanesthetized 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.

Decreased cognitive control over prepotent responses has been hypothesized to contribute to ethanol-induced behavioral disinhibition. However, the effects of ethanol on specific cognitive domains associated with decision making have not been extensively studied. We examined the impact of acute ethanol administration on cognitive performance of nonhuman primates. Studies were conducted using 0.2, 0.5, and 1 g/kg intravenous ethanol in rhesus macaques performing touch screen-based tasks examining stimulus discrimination, stimulus reversal, and stimulus response performance. The impact on attentional processing was also evaluated. Ethanol reduced the accuracy of reversal performance marginally at 0.2 g/kg and significantly at 0.5 g/kg. This effect was selective given an absence of impairment on the stimulus discrimination and stimulus response tasks at these doses. Performance on stimulus discrimination was impaired at 1.0 g/kg, which prevented determination of reversal performance. Analysis of post-error response times demonstrated that error processing was impaired at both 0.2 and 0.5 g/kg. Ethanol also increased the number of omissions and delayed responses on an attentional task, suggesting more frequent attentional lapses. These data demonstrate that cognitive function mediated by specific prefrontal cortical brain regions is particularly sensitive to ethanol and suggest specific cognitive mechanisms that may underlie harmful decisions made at low doses of ethanol.