Traumatic brain injury (TBI) affects more than 10 million individuals worldwide each year (~ 2.8 million in the USA) and results in long-term motor and cognitive deficits (e.g., reference learning and executive function). To combat this significant health care issue a variety of relatively invasive experimental therapeutic strategies have been attempted and have yielded limited translation to the clinic. Environmental enrichment (EE) is a non-invasive paradigm that promotes significant cognitive recovery and histological protection after experimental TBI and has the potential to mimic post-TBI clinical rehabilitation. The parent R01 was crafted to begin refining and optimizing EE after TBI so that it conformed temporally to clinical neurorehabilitation. The wealth of data lead to a preclinical model of neurorehabilitation that is temporally like the clinic in the sense that delaying EE for a week (i.e., rehabilitation) and providing only 4-hr per day (as common in the clinic) shows significant benefits. Overall, the findings provided significant support for EE as a potential model of neurorehabilitation, but additional empirical research is essential to learn more about its capabilities and limitations that ultimately strengthen its validity and applicability. Hence, the goal of this renewal is to utilize our delayed (7 day) and abbreviated (4 h day) EE model of neurorehabilitation, which we refer to as Rehab, to address questions that concern physiatrists. Five specific aims that are logical and crucial extensions of the parent grant are proposed: Aim 1a determine whether motor (beam and rotarod), cognitive (spatial learning & memory, and executive function using the attentional set shifting test that is analogous to the clinical Wisconsin card sorting task), and affective (open field test) benefits can be sustained after EE is withdrawn, and if so, for how long, Aim 1b determine if providing “refresher rehab” after the EE-induced benefits begin to wane will stabilize or re-strengthen benefits, Aims 2abc determine whether “bridging” delayed EE, which is initiated at 7- days after TBI, with a) [amantadine {10 mg/kg/day; i.p.}], b) aqua therapy [{two 90 s swim sessions}], or c) music exposure [(3 h per night of New Age, Ambient, or Classical - Mozart’s sonata for two pianos, K.448)] as adjunct therapies during the week after TBI will augment recovery relative to non-enriched or Rehab groups, and Aim 3 evaluate mechanisms for the bridge plus Rehab therapies. Completion of the aims will further advance a model of neurorehabilitation that mimics the real-world while addressing questions that continue to concern physiatrists, such as how long do the rehab benefits last once discontinued and can they be maintained or improved further with supplemental rehab? Can supplemental therapies before full rehab provide a better outcome? What mechanisms are involved in the effects observed? The refined model will significantly impact and advance rehabilitation-based research. Translatability of the findings will be facilitated further by optimizing the EE model in adult rats of both sexes and by assessing behavior with sensitive and clinically-relevant tests of motor and executive function both acutely and long-term.

Project Narrative Traumatic brain injury (TBI) is a significant health care issue that affects 10 million individuals each year throughout the world and about 2.8 million in United States for whom there are limited treatment options. While numerous invasive therapies have been evaluated, one non-invasive approach that has clinical relevance is environmental enrichment (EE), which is a therapeutic regimen that we have refined over the course of the parent grant to mimic clinical rehabilitation and has been shown to provide significant benefits relative to non- enriched housing. While EE is being optimized as a potential model of neurorehabilitation, additional empirical research is essential to learn more about its capabilities and limitations that ultimately strengthen its validity and applicability, and thus the goal of this renewal is to evaluate EE long-term, the effects of refresher rehabilitation, and bridge therapies that robustly expand on the parent grant successes that will fill gaps and expand our understanding of behavioral outcomes and mechanisms after TBI.