Effect of stress on the rehabilitation performance of rats with repetitive mild fluid percussion-induced traumatic brain injuries

Abstract

Animal models of traumatic brain injury (TBI) have shown that impaired motor and cognitive function can be improved by physical exercise. However, not each animal with TBI can be well rehabilitated at the same training intensity due to a high inter-subject variability. Hence, this paper presents a two-stage wheel-based mixed-mode rehabilitation mechanism by which the effect of stress on the rehabilitation performance was investigated. The mixed-mode rehabilitation mechanism consists of a two-week adaptive and a one-week voluntary rehabilitation program as Stages 1 and 2, respectively. In Stage 1, the common over and undertraining problem were completely resolved due to the adaptive design, and rats ran voluntarily over a 30-min duration in Stage 2. The training intensity adapted to the physical condition of all the TBI rats at all times in Stage 1, and then the self-motivated running rats were further rehabilitated under the lowest level of stress in Stage 2. For comparison purposes, another group of rats took a 3-week adaptive rehabilitation program. During the 3-week program, the rehabilitation performance of the rats were assessed using modified neurologic severity score (mNSS) and an 8-arm radial maze. Surprisingly, the group taking the mixed mode program turned out to outperform its counterpart in terms of mNSS. The mixed-mode rehabilitation mechanism was validated as an effective and efficient way to help rats restore motor, neurological and cognitive function after TBI. It was validated that the rehabilitation performance can be optimized under the lowest level of stress.

Keywords: Cognitive function; Exercise; Modified neurologic severity score; Neurologic status; Rehabilitation; Repetitive mild fluid percussion-induced traumatic brain injury; Short-term memory errors; Stress.

Fig. 1

A photo of the 3-channel running wheel equipped with an microcontroller and Infrared (IR) transmitter receiver pairs

Fig. 2

Mechanism of the 3-channel running wheel. a A wedge-shaped motor mount and b the hollowed portion for IR sensor deployment

Fig. 3

Main flow of the system operation

Fig. 4

Operation flow of a the adaptive mode, and b the voluntary mode

Fig. 5

Four timer interrupt service routines. Timer 0 in a counted down until the end of a training course, Timer 1 in b counted the number of times that the 45° and the 135° thresholds were hit, Timer 2 in c checked whether Position_135 reached 10, and Timer 3 in d checked whether Position_45 reached 10

Fig. 6

a Parameter configuration, and b real-time data display in a GUI

Fig. 7

Timeline of the experimental protocol. D, day; FPI, fluid percussion injury; mNSS, modified neurological severity score; TTC, triphenyl tetrazolium chloride

Fig. 8

A comparison on mNSS on Days -1, 7 and 28 among groups

Fig. 9

A comparison on a the latency, b the short-term memory errors, and c the long-term memory errors on Day -1, 7 and 28 among groups

Fig. 10

A comparison on the contusion volume on Day 28 among groups. Both the A&V and the Adaptive group significantly outperformed the Sedentary group, while the volumes in both groups were statistically indistinguishable, as shown in the zoomed in portion

Fig. 11

Corticosterone level comparison between the A&V and the Adaptive group

Fig. 12

A graph of the average running speed vs. time. TBI rats were trained in the adaptive mode over Weeks 1–2, while in the voluntary mode in Week 3

Fig. 13

Illustration of the running speed difference between the adaptive and the voluntary training