L1 Cell Adhesion Molecule Overexpression Down Regulates Phosphacan and Up Regulates Structural Plasticity-Related Genes Rostral and Caudal to the Complete Spinal Cord Transection.

L1 cell adhesion molecule (L1CAM) supports spinal cord cellular milieu after contusion and compression lesions, contributing to neuroprotection, promoting axonal outgrowth, and reducing outgrowth-inhibitory molecules in lesion proximity. We extended investigations into L1CAM molecular targets and explored long-distance effects of L1CAM rostral and caudal to complete spinal cord transection (SCT) in adult rats. L1CAM overexpression in neurons and glia after Th10/Th11 SCT was achieved using adeno-associated viral vector serotype 5 (AAV5) injected into an L1-lumbar segment immediately after transection.

Electrical Stimulation of Low-Threshold Proprioceptive Fibers in the Adult Rat Increases Density of Glutamatergic and Cholinergic Terminals on Ankle Extensor α-Motoneurons.

The effects of stimulation of low-threshold proprioceptive afferents in the tibial nerve on two types of excitatory inputs to α-motoneurons were tested. The first input is formed by glutamatergic Ia sensory afferents contacting monosynaptically α-motoneurons. The second one is the cholinergic input originating from V0c-interneurons, located in lamina X of the spinal cord, modulating activity of α-motoneurons via C-terminals.

The impact of training and neurotrophins on functional recovery after complete spinal cord transection: cellular and molecular mechanisms contributing to motor improvement.

Beneficial effects of locomotor training on the functional recovery after complete transection of the spinal cord indicate that in chronic spinal animals spontaneous recovery processes are enhanced and shaped by the training. The mechanisms of that use-dependent improvement are still not fully understood. This review tackles three aspects of this issue: (1) neurochemical attributes of functional improvement showing that concentrations of excitatory and inhibitory amino acids in the lumbar spinal segments, which were changed after transection, normalize after the training, or even raise beyond normal.

Overexpression of BDNF increases excitability of the lumbar spinal network and leads to robust early locomotor recovery in completely spinalized rats.

Strategies to induce recovery from lesions of the spinal cord have not fully resulted in clinical applications. This is a consequence of a number of impediments that axons encounter when trying to regrow beyond the lesion site, and that intraspinal rearrangements are subjected to. In the present study we evaluated (1) the possibility to improve locomotor recovery after complete transection of the spinal cord by means of an adeno-associated (AAV) viral vector expressing the neurotrophin brain-derived neurotrophic factor (BDNF) in lumbar spinal neurons caudal to the lesion site and (2) how the spinal cord transection and BDNF treatment affected neurotransmission in the segments caudal to the lesion site.

Enhancing proprioceptive input to motoneurons differentially affects expression of neurotrophin 3 and brain-derived neurotrophic factor in rat hoffmann-reflex circuitry.

The importance of neurotrophin 3 (NT-3) for motor control prompted us to ask the question whether direct electrical stimulation of low-threshold muscle afferents, strengthening the proprioceptive signaling, could effectively increase the endogenous pool of this neurotrophin and its receptor TrkC in the Hoffmann-reflex (H-reflex) circuitry. The effects were compared with those of brain-derived neurotrophic factor (BDNF) and its TrkB receptor. Continuous bursts of stimuli were delivered unilaterally for seven days, 80 min daily, by means of a cuff-electrode implanted over the tibial nerve in awake rats.

Different effects of spinalization and locomotor training of spinal animals on cholinergic innervation of the soleus and tibialis anterior motoneurons.

Cholinergic input modulates excitability of motoneurons and plays an important role in the control of locomotion in both intact and spinalized animals. However, spinal cord transection in adult rats affects cholinergic innervation of only some hindlimb motoneurons, suggesting that specificity of this response is related to functional differences between motoneurons. Our aim was therefore to compare cholinergic input to motoneurons innervating the soleus (Sol) and tibialis anterior (TA) motoneurons following spinal cord transection at a low-thoracic level.

Exercise-induced motor improvement after complete spinal cord transection and its relation to expression of brain-derived neurotrophic factor and presynaptic markers.

Background: It has been postulated that exercise-induced activation of brain-derived neurotrophic factor (BDNF) may account for improvement of stepping ability in animals after complete spinal cord transection. As we have shown previously, treadmill locomotor exercise leads to up-regulation of BDNF protein and mRNA in the entire neuronal network of intact spinal cord. The questions arise: (i) how the treadmill locomotor training, supplemented with tail stimulation, affects the expression of molecular correlates of synaptic plasticity in spinal rats, and (ii) if a response is related to BDNF protein level and distribution.

Glial inhibitors influence the mRNA and protein levels of mGlu2/3, 5 and 7 receptors and potentiate the analgesic effects of their ligands in a mouse model of neuropathic pain.

Metabotropic glutamate (mGlu) receptors, which are present on neurons and glial cells, have been shown to play a role in neuropathic pain. The present study sought to investigate how the glial inhibitors minocycline and pentoxifylline alter the effect that chronic constriction injury (CCI) has on the expression of mGlu receptors and on their associated ligands. RT-PCR analysis revealed that seven days after CCI, the mRNA levels of glial markers C1q and GFAP, as well as those of mGlu5 and mGlu3, but not mGlu7, were elevated in the lumbar spinal cord - ipsilateral to the injury.

Focal photothrombotic lesion of the rat motor cortex increases BDNF levels in motor-sensory cortical areas not accompanied by recovery of forelimb motor skills.

Brain infarct triggers neurodegeneration that often shades spontaneous plasticity, occurring in the areas related anatomically and functionally to the infarcted structures. Neurotrophins which promote neuronal survival and plasticity, may protect neurons and enhance remodeling of the remaining circuits, leading to restoration of function. In particular, the crucial role of brain-derived neurotrophic factor (BDNF) in cortical function is well documented.

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.

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.

Bcl-2 and Bax proteins are increased in neocortical but not in thalamic apoptosis following devascularizing lesion of the cerebral cortex in the rat: an immunohistochemical study.

The hypothesis that devascularization of somatosensory and motor cortex causes apoptosis in infarcted regions and in the linked thalamic nuclei was evaluated. To unravel whether Bcl-related proteins, known to regulate apoptosis, participate in neuronal and glial responses to devascularization, we analyzed immunohistochemically the distribution and intensity of staining of Bcl-2 and Bax proteins at different time points after lesion. Both early (up to 6 h) and late (1-7 days) responses were studied.

[The prospects for clinical use of neurotrophins in therapy].

In view of neuroprotective effects of neurotrophins and neurotrophic factors on the damaged nervous tissue clinical attempts have been made to use these proteins in the treatment of neurodegenerative diseases. However, the attempts were unsuccessful. We discuss the main causes of this failure and outline a new clinical prospect due to the growing understanding of the mechanisms underlying neurotrophin activity in the nervous system.

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.

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.

[Can neurotrophins help to repair an injured spinal cord?].

Basic information about neurotrophins, their receptors and distribution of these proteins in the central nervous system as well as their role in the development and maturity of the nervous system will be briefly reviewed in this chapter. Special emphasis will be given to the role of neurotrophins and their receptors after the damage of the nervous system. Finally, our recent data showing a possibility of increasing of endogenous pool of BDNF and NT-4 as well as their TrkB receptor in the spinal cord due to long-lasting, moderate locomotor training will be presented and discussed in terms of its clinical applicability.