Novel therapeutic concepts against cerebral ischemia focus on cell-based therapies in order to overcome some of the side effects of thrombolytic therapy. However, cell-based therapies are hampered because of restricted understanding regarding optimal cell transplantation routes and due to low survival rates of grafted cells. We therefore transplanted adult green fluorescence protein positive neural precursor cells (NPCs) either intravenously (systemic) or intrastriatally (intracerebrally) 6 hours after stroke in mice. To enhance survival of NPCs, cells were in vitro protein-transduced with TAT-heat shock protein 70 (Hsp70) before transplantation followed by a systematic analysis of brain injury and underlying mechanisms depending on cell delivery routes. Transduction of NPCs with TAT-Hsp70 resulted in increased intracerebral numbers of grafted NPCs after intracerebral but not after systemic transplantation. Whereas systemic delivery of either native or transduced NPCs yielded sustained neuroprotection and induced neurological recovery, only TAT-Hsp70-transduced NPCs prevented secondary neuronal degeneration after intracerebral delivery that was associated with enhanced functional outcome. Furthermore, intracerebral transplantation of TAT-Hsp70-transduced NPCs enhanced postischemic neurogenesis and induced sustained high levels of brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor, and vascular endothelial growth factor in vivo. Neuroprotection after intracerebral cell delivery correlated with the amount of surviving NPCs. On the contrary, systemic delivery of NPCs mediated acute neuroprotection via stabilization of the blood-brain-barrier, concomitant with reduced activation of matrix metalloprotease 9 and decreased formation of reactive oxygen species. Our findings imply two different mechanisms of action of intracerebrally and systemically transplanted NPCs, indicating that systemic NPC delivery might be more feasible for translational stroke concepts, lacking a need of in vitro manipulation of NPCs to induce long-term neuroprotection.

Rats perform texture discrimination during tactile exploration with their whiskers with high spatial and temporal precision. Although the peripheral mechanoreceptors provide tactile information with exquisite temporal resolution, physiological studies have suggested that this information might be lost at the cortical level. To address this discrepancy, multiunit and single-unit recordings were performed in the barrel cortex of isoflurane-anesthetized rats using continuous sinusoidal vibration of single whiskers at 15-700 Hz. In multiunit recordings, sustained phase-locked responses occurred up to vibration frequencies of 700 Hz, and 1:1 stimulus locking was observed up to 320 Hz. Wide-band responses of multiunits showed frequency encoding between 20 and 320 Hz. The discharge rates were not different for stimuli in the low-and high-frequency ranges, but they were significantly lower for non-phase-locked responses to high-frequency vibration. Response adaptation was present in only 25% of the cases, whereas in the majority of cases, entrainment to the vibratory frequency remained constant or even increased with stimulus duration. Increased entrainment to high-frequency stimulation was accompanied by the emergence of induced activity in the gamma-band range. Analysis of single-unit activity revealed that phase locking to vibratory stimuli was more precise than that observed for the multiunit responses. The results show that whisker vibrations at frequencies above 100 Hz are faithfully encoded by sustained phase-locked responses of cortical neurons under isoflurane anesthesia. It is conceivable that the awake animal makes use of the tactile signals at even much higher frequencies, which can be provided by the peripheral mechanoreceptors during texture discrimination.

Rats probe objects with their whiskers and make decisions about sizes, shapes, textures and distances within a few tens of milliseconds. This perceptual analysis requires the processing of tactile high-frequency object components reflecting surface roughness. We have shown that neurons in the barrel cortex of rats encode high-frequency sinusoidal vibrations of whiskers for sustained periods when presented with constant amplitudes and frequencies. In a natural situation, however, stimulus parameters change rapidly when whiskers are brushing across objects. In this study, we therefore analysed cortical responses to vibratory movements of single whiskers with rapidly changing amplitudes and frequencies. The results show that different neural codes are employed for a processing of stimulus parameters. The frequency of whisker vibration is encoded by the temporal pattern of spike discharges, i.e., the phase-locked responses of barrel cortex neurons. In addition, oscillatory gamma band activity was induced during high-frequency stimulation. The pivotal descriptor of the amplitude of whisker displacement, the velocity, is reflected in the rate of spike discharges. While phase-locked discharges occurred over the entire range of frequencies tested (10-600 Hz), the discharge rate increased with stimulus velocity only up to about 60 µm/ms, saturating at a mean rate of ~117 spikes/s. In addition, the results show that whisker movements of more than 500 Hz bandwidth may be encoded by phase-locked responses of small groups of cortical neurons. Thus, even single whiskers may transmit information about wide ranges of textural components owing to their set of different types of hair follicle mechanoreceptors.