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.

Aripiprazole and environmental enrichment independently improve functional outcome after cortical impact injury in adult male rats, but their combination does not yield additional benefits.

Typical antipsychotic drugs (APDs) with D2antagonistic properties impede functional outcome after experimental traumatic brain injury (TBI) and reduce the effectiveness of environmental enrichment (EE). Here we test the hypothesis that aripiprazole (ARIP), an atypical APD with partial D2and 5-HT1Areceptor agonist activities will improve recovery after TBI and when combined with EE will further enhance the benefits. Anesthetized adult male rats received either a controlled cortical impact of moderate severity or sham injury and then were randomly assigned to EE or standard (STD) housing and once daily intraperitoneal injections of ARIP (0.1 mg/kg) or vehicle (VEH; 1.0 mL/kg) beginning 24 h after injury for 19 days. Motor (beam-walking time and beam-walk score) and cognitive (acquisition of spatial learning and memory) outcomes were assessed on post-operative 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 housing or treatment, so the data were pooled. The SHAM group performed better than all TBI groups on motor and spatial learning (p < 0.05) but did not differ from either EE group on memory retention. Regarding TBI, both EE groups improved motor and cognitive outcomes vs. the VEH-treated STD group (p < 0.05) but did not differ from one another (p > 0.05). The ARIP-treated STD group performed better than the VEH-treated STD group on beam-walk score and spatial learning (p < 0.05), but not beam-walking time or memory retention (p > 0.05). Cortical lesion volume was smaller in all treated groups compared to the TBI + STD + VEH group (p < 0.05). The data replicate previous work and extend the findings by demonstrating that 1) ARIP promotes recovery after TBI, but combining treatments does not yield additional benefits, which is contrary to the hypothesis, and 2) unlike APDs that exhibit D2 receptor antagonism, ARIP does not impede rehabilitation (i.e., EE).

Intermittent Administration of Haloperidol after Cortical Impact Injury Neither Impedes Spontaneous Recovery Nor Attenuates the Efficacy of Environmental Enrichment.

The administration of haloperidol (HAL) once-daily for 19 days after experimental traumatic brain injury (TBI) impedes recovery and attenuates the efficacy of environmental enrichment (EE). However, it is unknown how intermittent administration of HAL affects the recovery process when paired with EE. Addressing the uncertainty is relevant because daily HAL is not always warranted to manage TBI-induced agitation in the clinic, and indeed intermittent therapy may be a more common approach. Hence, the aim of the study was to test the hypothesis that intermittent HAL would neither impair recovery in standard (STD)-housed controls nor attenuate the efficacy of EE. Anesthetized adult male rats received a cortical impact or sham injury and then were housed in STD or EE conditions. Beginning 24 h later, HAL (0.5 mg/kg; intraperitoneally [i.p.]) was administered either once-daily for 19 days or once every other day, whereas vehicle (VEH; 1 mL/kg; i.p.) was administered once daily. Motor performance and cognition were assessed on post-injury days 1-5 and 14-19, respectively. Cortical lesion volume was quantified on day 21. SHAM controls performed better than all TBI groups on motor and spatial learning [p < 0.05], but did not differ from the TBI + EE + daily VEH group on memory retention [p > 0.05]. The TBI + EE + daily VEH and TBI + EE + intermittent HAL groups did not differ from one another on beam-walk or spatial learning [p > 0.05], and both performed better than all other TBI groups [p < 0.05]. In contrast, the TBI + STD + daily HAL group performed worse than all TBI groups on spatial learning [p < 0.05]. No difference in any endpoint was revealed between the TBI + STD + intermittent HAL and TBI + STD + daily VEH groups [p > 0.05]. The results support the hypothesis that HAL is not detrimental when provided intermittently. If translatable to the clinic, intermittent HAL may be used to control TBI-induced agitation without negatively affecting spontaneous recovery or rehabilitative efficacy.

Albeit nocturnal, rats subjected to traumatic brain injury do not differ in neurobehavioral performance whether tested during the day or night.

Behavioral assessments in rats are overwhelmingly conducted during the day, albeit that is when they are least active. This incongruity may preclude optimal performance. Hence, the goal of this study was to determine if differences in neurobehavior exist in traumatic brain injured (TBI) rats when assessed during the day vs. night. The hypothesis was that the night group would perform better than the day group on all behavioral tasks. Anesthetized adult male rats received either a cortical impact or sham injury and then were randomly assigned to either Day (1:00-3:00p.m.) or Night (7:30-9:30p.m.) testing. Motor function (beam-balance/walk) was conducted on post-operative days 1-5 and cognitive performance (spatial learning) was assessed on days 14-18. Corticosterone (CORT) levels were quantified at 24h and 21days after TBI. No significant differences were revealed between the TBI rats tested during the Day vs. Night for motor or cognition (p's<0.05). CORT levels were higher in the Night-tested TBI and sham groups at 24h (p<0.05), but returned to baseline and were no longer different by day 21 (p>0.05), suggesting an initial, but transient, stress response that did not affect neurobehavioral outcome. These data suggest that the time rats are tested has no noticeable impact on their performance, which does not support the hypothesis. The finding validates the interpretations from numerous studies conducted when rats were tested during the day vs. their natural active period.

Tracing neuronal circuits in transgenic animals by transneuronal control of transcription (TRACT).

Understanding the computations that take place in brain circuits requires identifying how neurons in those circuits are connected to one another. We describe a technique called TRACT (TRAnsneuronal Control of Transcription) based on ligand-induced intramembrane proteolysis to reveal monosynaptic connections arising from genetically labeled neurons of interest. In this strategy, neurons expressing an artificial ligand ('donor' neurons) bind to and activate a genetically-engineered artificial receptor on their synaptic partners ('receiver' neurons). Upon ligand-receptor binding at synapses the receptor is cleaved in its transmembrane domain and releases a protein fragment that activates transcription in the synaptic partners. Using TRACT in Drosophila we have confirmed the connectivity between olfactory receptor neurons and their postsynaptic targets, and have discovered potential new connections between neurons in the circadian circuit. Our results demonstrate that the TRACT method can be used to investigate the connectivity of neuronal circuits in the brain.