Comparing the predictive value of multiple cognitive, affective, and motor tasks after rodent traumatic brain injury

Controlled cortical impact injury (CCI) is a widely-used, clinically-relevant model of traumatic brain injury (TBI). Although functional outcomes have been used for years in this model, little work has been done to compare the predictive value of various cognitive and sensorimotor assessment tests, singly or in combination. Such information would be particularly useful for assessing mechanisms of injury or therapeutic interventions. Following isoflurane anesthesia, C57BL/6 mice were subjected to sham, mild (5.0 m/sec), moderate (6.0 m/sec), or severe (7.5 m/sec) CCI. A battery of behavioral tests were evaluated and compared, including the standard Morris water maze (sMWM), reversal Morris water maze (rMWM), novel object recognition (NOR), passive avoidance (PA), tail-suspension (TS), beam walk (BW), and open-field locomotor activity. The BW task, performed at post-injury days (PID) 0, 1, 3, 7, 14, 21, and 28, showed good discrimination as a function of injury severity. The sMWM and rMWM tests (PID 14-23), as well as NOR (PID 24 and 25), effectively discriminated spatial and novel object learning and memory across injury severity levels. Notably, the rMWM showed the greatest separation between mild and moderate/severe injury. PA (PID 27 and 28) and TS (PID 24) also reflected differences across injury levels, but to a lesser degree. We also compared individual functional measures with histological outcomes such as lesion volume and neuronal cell loss across anatomical regions. In addition, we created a novel composite behavioral score index from individual complementary behavioral scores, and it provided superior discrimination across injury severities compared to individual tests. In summary, this study demonstrates the feasibility of using a larger number of complementary functional outcome behavioral tests than those traditionally employed to follow post-traumatic recovery after TBI, and suggests that the composite score may be a helpful tool for screening new neuroprotective agents or for addressing injury mechanisms.