Locomotor exercise alters expression of pro-brain-derived neurotrophic factor, brain-derived neurotrophic factor and its receptor TrkB in the spinal cord of adult rats.

Previous evidence indicates that locomotor exercise is a powerful means of increasing brain-derived neurotrophic factor (BDNF) and its signal transduction receptor TrkB mRNA levels, immunolabeling intensity and number of BDNF- and TrkB-immunopositive cells in the spinal cord of adult rats but the contribution of specific cell types to changes resulting from long-term activity is unknown. As changes in BDNF protein distribution due to systemic stimuli may reflect either its in-situ synthesis or its translocation from other sources, we investigated where BDNF and TrkB mRNA are expressed in the spinal lumbar segments. We report on the cell types defined by size, BDNF mRNA levels and number of cells with TrkB transcripts in sedentary and exercised animals following 28 days of treadmill walking. In the majority of cells, exercise increased perikaryonal levels of BDNF mRNA but did not affect TrkB transcript levels. Bidirectional changes in a number of TrkB mRNA-expressing cells occurred in small groups of ventral horn neurons. An increase in BDNF transcripts was translated into changes in pro-BDNF and BDNF levels. A 7-day walking regimen increased BDNF protein levels similarly to 28-day treadmill walking. Our observations indicate that long- and short-term locomotor activity of moderate intensity produce stimuli sufficient to recruit a majority of spinal cells to increased BDNF synthesis, suggesting that continuous tuning of pro-BDNF and BDNF levels permits spinal networks to undergo trophic modulation not requiring changes in TrkB mRNA supply.

Confocal visualization of the effect of short-term locomotor exercise on BDNF and TrkB distribution in the lumbar spinal cord of the rat: the enhancement of BDNF in dendrites?

Locomotor exercise increases neurotrophin BDNF and its receptor TrkBFL expression in the lumbar spinal cord. Involvement of BDNF/TrkBFL in synaptic transmission raises the questions which intracellular compartments are involved in this upregulation and whether exercise leads to redistribution of these proteins related to the duration of exercise. We have investigated the influence of short-term (7 days) locomotor exercise (ST) on intracellular distribution of BDNF and TrkBFL in the rat lumbar spinal cord comparing it with the effects of long-term (28 days) exercise (LT) described earlier. Immunofluorescence (IF) of proteins was analyzed with confocal microscopy. ST exercise caused a redistribution of perikaryonal BDNF IF toward periphery resulting in an increase of dendritic signal. In contrast to an enhancement of perikaryonal BDNF staining following LT, no increase of BDNF IF in cell bodies was observed after ST. An increase of TrkBFL IF in oligodendrocytes was consistent with that caused by LT. The fibers of TrkBFL IF oligodendrocytes surrounding the largest neurons were in close apposition to neuronal membrane. We propose that ST exercise causes (1) BDNF translocation to dendrites and/or local dendritic synthesis to serve increased synaptic activity (2) sensitization of oligodendroglia to BDNF mediated responses.

Exercise increases mRNA levels for adhesion molecules N-CAM and L1 correlating with BDNF response.

In situ hybridization was used to evaluate whether long-term moderate locomotor exercise, which up-regulates BDNF and TrkB levels in the spinal gray matter of the adult rat, similarly influences the expression of the cell adhesion molecules N-CAM and L1. Exercise doubled the level of N-CAM mRNA hybridization signal in the lumbar spinal gray. The increase in L1 mRNA was less consistent. N-CAM mRNA levels slightly increased in the white matter. BDNF mRNA levels also increased in cells of the ventral horn and the white matter due to the exercise. These results suggest that exercise-induced rearrangements of the spinal network involve N-CAM, L1 and BDNF, crucial in different aspects of synaptic plasticity and synapse formation.

Long-term locomotor training up-regulates TrkB(FL) receptor-like proteins, brain-derived neurotrophic factor, and neurotrophin 4 with different topographies of expression in oligodendroglia and neurons in the spinal cord.

Neurotrophins are potent regulators of neuronal survival, maintenance, and synaptic strength. In particular, brain-derived neurotrophic factor (BDNF), acting through full-length TrkB receptor (TrkB(FL)), is implicated in the stimulation of neurotransmission. Physical activity has been reported to increase BDNF expression in the brain and spinal cord. In this study we have evaluated the hypothesis that activation of a spinal neuronal network, due to exercise, affects the entire spinal neurotrophin system acting via TrkB receptors by modulation of BDNF, neurotrophin 4 (NT-4), and their TrkB receptor proteins. We investigated the effect of treadmill walking (4 weeks, 1 km daily) on distribution patterns and response intensity of these proteins in the lumbar spinal cord of adult rats. Training enhanced immunoreactivity (IR) of both neurotrophins. BDNF IR increased in cell processes of spinal gray matter, mainly in dendrites. NT-4 IR was augmented in the white matter fibers, which were, in part, of astrocytic identity. Training strongly increased both staining intensity and number of TrkB(FL)-like IR small cells of the spinal gray matter. The majority of these small cells were oligodendrocytes, representing both their precursor and their mature forms. In contrast, training did not exert an effect on expression of the truncated form of TrkB receptor in the spinal cord. These results show that both neuronal and nonneuronal cells may be actively recruited to BDNF/NT-4/TrkB(FL) neurotrophin signaling which can be up-regulated by training. Oligodendrocytes of the spinal gray matter were particularly responsive to exercise, pointing to their involvement in activity-driven cross talk between neurons and glia.