Millions of persons every year are affected by traumatic brain injury (TBI), and currently no therapies have shown efficacy in improving outcomes clinically. Recent research has suggested that enriched environments (EE), embryonic neural stem cells (eNSC), and progesterone (PROG) improve functional outcomes after TBI, and further, several investigators have suggested that a polytherapuetic approach may have greater efficacy than a single therapy. The purpose of the current study was to determine if varying combinations of post-injury EE, progesterone therapy, or eNSC transplantation would improve functional outcomes over just a single therapy. A controlled cortical impact was performed in rats to create a lesion in the medial frontal cortex. The rats were then placed in either EE or standard environments and administered 10 mg/kg progesterone or vehicle injections 4 h post-injury and every 12 h for 72 h after the initial injection. Seven days after the surgery, rats were transplanted with either eNSCs or media. Rats were then tested on the open field test, Barnes maze, Morris water maze, and Rotor-Rod tasks. Improved functional outcomes were shown on a majority of the behavioral tasks in animals that received a combination of therapies. This effect was especially prominent with therapies that were combined with EE. Immunohistochemistry showed that the transplanted eNSCs survived, migrated, and displayed neural phenotypes. These data suggest that a poly-therapeutic approach after TBI improves functional recovery to a greater magnitude. Moreover, when polytherapies are combined with EE, the effects on recovery are enhanced, leading to greater recovery of function.

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Purpose: Anxiety-like (ANX) and depression-like (DEP) symptoms are common consequences of traumatic brain injury (TBI). Environmental enrichment (EE) attenuates many deficits, though its impact on ANX and DEP symptoms has yet to be described. Methods: Adult male Long-Evans rats were subject to a medial frontal cortex (mFC) cortical impact injury or sham preparation, then placed into EE or standard housing (SE). ANX symptoms were analyzed using the open field test (OFT) and elevated plus maze (EPM). The forced swim task (FST) and sucrose consumption task (SCT) were used to quantify DEP symptoms. In order to measure changes in spatial learning and motor performance, the Barnes maze (BM) and rotor rod (RR) were utilized. Results: Damage to the mFC resulted in functional losses in motor and cognitive behavior and an increase in ANX and DEP symptoms. Placement of injured rats into the EE improves motor functioning after TBI and resulted in an decreased latency to locate the escape box in the BM. Though the application of an EE attenuated deficits in BM and RR performance, the ANX and DEP behavioral symptoms persisted. Conclusions: Additional therapeutic approaches paired with EE may be necessary to address all functional changes post-TBI. Additionally, no single behavioral assessment appears to clearly identify symptoms of ANX or DEP in rats following TBI, however utilizing multiple tests can be potentially confounding. als who survive TBI report cognitive and behavioral deficits, including impaired cognition and memory, but also an increased prevalence of anxiety and depression (Jones et al.