Orexin A modulates neuronal activity of the rodent suprachiasmatic nucleus in vitro.

In mammals, as in rats and mice used in the present study, the major internal timekeeping mechanism is located in the suprachiasmatic nucleus (SCN). It is composed of a complex tissue of multiple, individual oscillator cells that drive numerous physiological and endocrine processes via an electrical and humoral output. Several afferent input systems can interact with the clock mechanism and lead to phase-resetting actions. The recent discovery of orexin-containing fibers in the SCN region and the presence of orexin receptors in the SCN prompted us to investigate the possible role of orexin in the SCN. Multielectrode array recordings from dispersed SCN neurons revealed that orexin A dose-dependently enhanced the extracellularly recorded neuronal activity of many neurons (38%), whereas other neurons were inhibited (28%). The influence of orexin A on neuronal activity in the SCN was confirmed by whole-cell patch-clamp recordings from brain slices and dispersed cell cultures. Orexin A caused significant changes in the frequency but not mean amplitude or decay time constant of spontaneous inhibitory postsynaptic currents (sIPSCs). Low concentrations of orexin evoked an increase of sIPSCs, whereas the highest concentration predominantly caused a decrease of sIPSCs. The effects of orexin A on inhibitory postsynaptic currents were prevented by the orexin 1 receptor antagonist SB 334867 and also reduced in the presence of tetrodotoxin. Long-term recordings of the discharge rate of SCN neurons revealed that orexin A is able to induce phase shifts in cultured SCN neurons as well as in organotypic brain slices.

Additive neuroprotective effect of Ketanserin and Ipsapirone on the hippocampal damage after transient forebrain ischemia in the Mongolian gerbil.

Modulation of the serotonin (5HT) system via 5HT1A or 5HT2A receptors exerts a neuroprotective effect on delayed neuronal death after transient forebrain ischemia. We tested the hypothesis that a 5HT1A agonist (Ipsapirone) in combination with a 5HT2A receptor antagonist (Ketanserin) could improve the neuroprotection. Starting 15 min prior to transient forebrain ischemia in the gerbil model, different doses of Ipsapirone (1, 2, 3 mg) and Ketanserin (5 mg/kg) were applied intraperitoneally. Seven days after ischemia, surviving pyramidal cells of the CA1 sector of the hippocampus were counted. The significance of the differences between the means was assessed by an analysis of variance according to the Scheffé test. The hippocampal cell damage was analyzed by histological evaluation. Combined application of Ipsapirone and Ketanserin led to a dose-dependent additive effect with up to 83% preservation of hippocampal CA1 neurons (P<0.001). The results of the present study suggest that the combination of 5HT1A receptor agonists and 5HT2A receptor antagonists might be an effective tool for the treatment of cerebral ischemia.

Modulation of soleus H-reflexes during gait in healthy children.

During locomotion spinal short latency reflexes are rhythmically modulated and depressed compared to rest. In adults this modulation is severely disturbed after bilateral spinal lesions indicating a role for supra-spinal control. Soleus reflex amplitudes are large in the stance phase and suppressed in the swing phase contributing to the reciprocal muscle activation pattern required for walking. In early childhood the EMG pattern during gait underlies an age-dependent process changing from co-contraction of agonists and antagonists to a reciprocal pattern at the age of 5-7 years. It is unknown whether at this stage apart from the EMG also reflexes are modulated, and if so, whether the reflex modulation is fully mature or still underlies an age-dependent development. This may give important information about the maturation of CNS structures involved in gait control. Soleus Hoffmann H-reflexes were investigated in 36 healthy children aged 7-16 years during treadmill walking at 1.2 km/h and 3.0 km/h. At 7 years old a rhythmic modulation similar to adults was observed. The H-reflex size during the stance phase decreased significantly with age while the maximum H-reflex (H (max)) at rest remained unchanged. At 3.0 km/h H-reflexes were significantly larger during the stance phase and smaller during the swing phase as compared to 1.2 km/h but the age-dependent suppression was observed at both walking velocities. In conclusion H-reflex modulation during gait is already present in young children but still underlies an age-dependent process independent of the walking velocity. The finding that the rhythmic part of the modulation is already present at the age of 7 years may indicate that the supra-spinal structures involved mature earlier than those involved in the tonic reflex depression. This may reflect an increasing supra-spinal control of spinal reflexes under functional conditions with maturation.