Exercise-induced improvement in cognitive performance after traumatic brain injury in rats is dependent on BDNF activation

Abstract

We have previously shown that voluntary exercise upregulates brain derived neurotrophic factor (BDNF) within the hippocampus and is associated with an enhancement of cognitive recovery after a lateral fluid percussion injury (FPI). In order to determine if BDNF is critical to this effect we used an immunoadhesin chimera (TrkB-IgG) that inactivates free BDNF. This BDNF inhibitor was administered to adult male rats two weeks after they had received a mild fluid percussion injury (FPI) or sham surgery. These animals were then housed with or without access to a running wheel (RW) from post-injury-day (PID) 14 to 20. On PID 21, rats were tested for spatial learning in a Morris Water Maze. Results showed that exercise counteracted the cognitive deficits associated with the injury. However this exercise-induced cognitive improvement was attenuated in the FPI-RW rats that were treated with TrkB-IgG. Molecules important for synaptic plasticity and learning were measured in a separate group of rats that were sacrificed immediately after exercise (PID 21). Western blot analyses showed that exercise increased the mature form of BDNF, synapsin I and cyclic-AMP response-element-binding protein (CREB) in the vehicle treated Sham-RW group. However, only the mature form of BDNF and CREB were increased in the vehicle treated FPI-RW group. Blocking BDNF (pre administration of TrkB-IgG) greatly reduced the molecular effects of exercise in that exercise-induced increases of BDNF, synapsin I and CREB were not observed. These studies provide evidence that BDNF has a major role in exercise's cognitive effects in traumatically injured brain.

Figures

Fig. 1. Swimming latency in the Morris Water Maze task

Rats were tested for one session daily beginning on post-injury day 21. Time between sessions was 24 hours. A significant decrease in latency across sessions was observed in fluid-percussion injury (FPI) and sham groups (*p

Fig. 2. Effects of exercise on the rate of acquisition on the Morris Water Maze task

A high Criterion Score indicates that the rat was able to learn the task during the first days of training according to a strict learning criterion. Criterion scores were significantly higher in the saline treated (Sal) exercised (RW) groups compared to the sedentary (Sed) groups. Fluid-percussion injured (FPI) rats that received TrkB-IgG did not benefit from exercise. Each value represents the mean ± SEM,

Fig. 3. Effects of exercise on hippocampal brain derived neurotrophic factor (BDNF)

(A) Levels of precursor (proBDNF) and mature (mBDNF) forms of BDNF. The levels of mBDNF were significantly increased in the saline treated (Sal) exercised (RW) groups compared to the sedentary (Sed) groups. Fluid-percussion injured (FPI) rats that received TrkB-IgG did not benefit from exercise. * P

Fig. 4. Effects of exercise on hippocampal synapsin I

(A) Levels of phosphorylated synapsin I. The levels of synapsin I were significantly increased in the saline treated (Sal) exercised (RW) sham group compared to the sedentary (Sed) shams. The exercise-induced increase in synapsin was not observed after a fluid percussion injury (FPI). * P

Fig. 5. Effects of exercise on hippocampal CREB

(A) Levels of phosphorylated CREB. The levels of CREB were significantly increased in the saline treated (Sal) exercised (RW) groups compared to the sedentary (Sed) groups. Fluid-percussion injured (FPI) rats that received TrkB-IgG did not benefit from exercise. * P