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Reactive oxygen species (ROS) are thought to be involved in many forms of programmed cell death. The role of ROS in cell death caused by oxidative glutamate toxicity was studied in an immortalized mouse hippocampal cell line (HT22). The causal relationship between ROS production and glutathione (GSH) levels, gene expression, caspase activity, and cytosolic Ca2+ concentration was examined. An initial 5-10-fold increase in ROS after glutamate addition is temporally correlated with GSH depletion. This early increase is followed by an explosive burst of ROS production to 200-400-fold above control values. The source of this burst is the mitochondrial electron transport chain, while only 5-10% of the maximum ROS production is caused by GSH depletion. Macromolecular synthesis inhibitors as well as Ac-YVAD-cmk, an interleukin 1beta-converting enzyme protease inhibitor, block the late burst of ROS production and protect HT22 cells from glutamate toxicity when added early in the death program. Inhibition of intracellular Ca2+ cycling and the influx of extracellular Ca2+ also blocks maximum ROS production and protects the cells. The conclusion is that GSH depletion is not sufficient to cause the maximal mitochondrial ROS production, and that there is an early requirement for protease activation, changes in gene expression, and a late requirement for Ca2+ mobilization. Show less

On the basis of characteristics of the exteroceptive reflexes and of the instincts it was shown that instinct behaviour developed from reflex characteristics (local characteristic of the stimuli, pos. and neg. taxis, habituation, conditioning). Most similarities are found between reflex and avoidance instinct behaviour (instincts for excretion, thermoregulation, body care, pain avoidance and safety). Except the safety instinct, all others react on stimuli, characterised by the localisation of the receptors. In the safety instinct the structure of the stimulus becomes important, together with the growing importance of the third dimension. This instinct shows also for the first time a variability of the threshold with spontaneous remaining low for some time after stimulation of the system. Inverse the gain instincts (nutrition, sex and social instinct). Here the threshold falls spontaneously, when stimuli are lacking and raises, when stimuli are found. The spontaneous motor expression of the lowering of the threshold is the appetite behaviour. It means seeking stimuli, which will be gained by elements of the initial and terminal success behaviour. The successfull nutritional and sexual behaviour is stopped by success inhibition, whereas the social instinct remains in the terminal success behaviour with group dynamic hierarchy, with imitating and helping behaviour. Overchanging of the gain instincts provokes avoidance behaviour with constant threshold. The neural systems of most reflexes lie distributed in the spinal cord and brainstem, the ones of the instincts in the limbic part of the brain, the nutrition and sex instinct with a hypothalamic pacemaker. Simultaneous activation of two or many instinct motivation systems result, not comparable with the direct reflex interaction, in interactions on the level of the global interaction, in interactions on the level of the global integration (summation, mixture, synthesis, rest, oscillation, intention) which projects the activity patterns via the motor cortex to the peripheral neurons. There it is completed by the reflexes. The hormonal and vegetative projection instead go directly to the end organs. The motivation is responsible for the subjective experience, the dominating integration with its motor projection for the instinct behaviour. Show less