Similar to environment enrichment, stress is another important paradigm that researchers often used to study the association of environmental factors and AD pathology in AD models. Stress, an unavoidable condition of human experience including both major life events and the methylation level specific kind problems of daily life, is known to affect the body��s physiology, immunological response and endocrine system. The most popular experimental procedure to induce stress in animals relies on the use of restraint, which has the advantage of being straightforward and painless. The experiments which subjected the mice of AD models to behavioral stress also yielded inconsistent results in terms of extracellular plaque pathology. For example, Devi et al found that stress aggravated b-amyloidogenesis in hippocampus but not cortex, and in female but not male mice. In contrast, Lee et al reported that the stress accelerates b-amyloidogenesis in not only cortex and hippocampus but also both female and male animals. For example, the treatment duration varies ranging from a consecutive several days to several months. No comparative studies of the relative merits favoring any duration have been reported. In this study, we investigated the effects of two months of immobilization on the Ab plaque formation in TgCRND8 mice. Despite an intensive activation of the neurons of hypothalamic PVN and SON and marked increased levels of corticosterone, the stress marker, under restraint stress, this treatment paradigm failed categorically to modify Ab pathology in the brains of TgCRND8 mice with treatment being initiated at the age of either 1 or 4 months. In this study, we applied 1- and 4-month-old TgCRND8 animals since the animals at the age of 1 month were not old enough to have amyloid plaque pathology in cortex and hippocampus, whereas the animals at the age of 4 month had an observable amyloid plaque pathology in their brains. These results indicate that the restraint stress failed to accelerate not only the onset of amyloid plaque pathology, but also its progression. These results were in stark contrast to those of Lee et al who found the aggravation of Ab pathology in restraint-treated Tg2576 under certain circumstances, restraint will not produce a stress response which may be due to insufficient intensity and duration of the restraint. In the study of Lee et al, AD mice were exposed to restraint for 2 h daily for consecutive 16 days. However, the animals in the present study were subjected to restraints for 6 h daily for 2 months, and the intensity of treatment was stronger and duration of treatment is much longer than those in the previous study. Thus, difference in intensity and duration of restraint seemed not to be the reason for the observed difference. To further confirm that the restraint produced a stress response in the restrained mice, we examined the global consequence of restraint stress in hypothalamus of neuroendocrine system, and found that restraint stress induced activation of oxytocin neurons in PVN and SON of hypothalamus as evidenced by induction of c-fos expression. It has been suggested that oxytocin may regulate stress-induced corticotropin-releasing hormone gene expression. The different genotypes of the AD models may account for the different results seen in the studies of Lee et al and ours. In line with this, discrepancies in the reported results about studying the effects of environmental enrichment on Ab pathology among different research groups have been reported.