During aging, many neurons in the septohippocampal cholinergic system degenerate and may cause memory loss. It is possible that hyper-reactivity to stressful stimuli can also accelerate neuron degeneration in this system. Our aim is to learn: (a) whether or not the characteristic stress-induced adaptive changes in cholinergic neurons are altered in aged rats; (b) how age-related changes in neurotransmitter systems converging in the septum influence the septohippocampal cholinergic system; (c) how age-related changes in the regulation of the glucocorticoid hormonal system affect the septohippocampal cholinergic system; and (d) how stress-induced changes in specific stress-responsive proteins, including polyamine metabolism, are involved in neuronal function. The results so far indicate that age-related degeneration of cholinergic neurons is accompanied by compensatory changes in neighboring neurons to prevent the loss of cholinergic neurotransmission, and that high glucocorticoid levels can accelerate the degeneration rate of cholinergic neurons. Our recent studies also indicate that glutamatergic neurons increase their activity in response to stress in a region selective manner. This activation is probably dependent on the activation of ascending neuronal inputs, such as dopamine neurons, that terminate in the septum. We recently examined the effects of various regimens of lithium chloride treatment on dexamethasone-induced increases in brain polyamine metabolizing enzymes. In contrast to peripheral tissues, where acute lithium treatment suppresses the increase in polyamine biosynthesis, in the brain, only chronic treatment was effective in preventing this increase.