Traumatic brain injury (TBI) affects 1.7 million individuals in the United States each year causing long- term motor and cognitive disabilities. To combat this significant health care issue a variety of relatively invasive experimental therapeutic strategies have been attempted, but 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. However, a shortcoming of the typical EE paradigm is that it consists of immediate and continuous exposure after TBI, which is inconsistent with the time frame of clinical rehabilitation where physiotherapy is initiated later after TBI (i.e., after critical care treatment) and with limited exposure. Hence, refining the typical EE paradigm in terms of time of initiation and duration of physiotherapeutic exposure after TBI so that it conforms closer to clinical rehabilitation practice is paramount for advancement of a relevant preclinical model of neurorehabilitation that can be applied to the TBI setting to facilitate translatable research. The translatability will be strengthened further by developing the model in both males and females and by adding a pharmacotherapy to augment rehabilitation. To this end, four specific aims are proposed.
Aim 1 will determine the latest time after moderate TBI (i.e., 3, 7, or 10 days; clinically-relevant temporal window) when an abbreviated 6-hr dose of EE, which is rehabilitation-relevant, can be administered and still effectively improve motor (rotarod), cognitive (Morris water maze and novel object recognition), and histological outcome (CA1/3 cell survival and cortical lesion volume), as well as induce neuroplasticity (synaptophysin, PSD-95, and neurogenesis quantified with immunohistochemistry and/or Western blot) that will correlate with neurobehavioral outcomes.
Aim 2 will evaluate the long term effects of this approach by withdrawing EE at the completion of the initial behavioral assessments (i.e., 3 weeks) and then retesting for all behaviors at 3, 6, and 12 months.
Aim 3 will evaluate whether the benefits conferred by the EE paradigm with the longest effective time delay post-TBI from Aim 2 can be enhanced or maintained by providing refresher rehab for 2 weeks before retesting at 3, 6, & 12 months.
Aim 4 a will determine whether combining buspirone, a clinically-relevant pharmacotherapy and shortened EE paradigms of 2 or 4 hours is capable of conferring benefits and Aim 4b will evaluate the long-term effects of this combinational approach. Completion of the proposed aims will yield a preclinical model of rehabilitation that mimics the real world situation of the TBI patient who 1) will not engage in rehabilitation until after criticl care and once engaged in therapy will receive limited amounts each day, and 2) will receive rehabilitation plus a pharmacotherapy, which is common in the clinic. The refined model will significantly impact and advance rehabilitation research by providing insight into timing and therapeutic parameters that are clinically relevant.
Traumatic brain injury (TBI) is a significant health care issue that affects 1.7 million individuals each year in the United States and for which there are limited treatment options available. While numerous invasive therapies have been evaluated (e.g., hypothermia), one non-invasive approach that has clinical relevance is environmental enrichment (EE), which is a therapeutic regimen that mimics rehabilitation and has been shown to provide significant benefits relative to non-enriched housing. However, neither the limited amounts (i.e.,'doses') nor time of initiation (temporal window) of EE that may benefit outcome have been fully investigated on subsequent recovery after TBI, and thus the aim of this R01 application is to evaluate these parameters in males and females to determine what combination of timing and duration of physiotherapeutic exposure will lead to a novel rehabilitation-relevant model of EE that could have an immediate impact on translatable rehabilitation research.
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