Chronic stress has been shown to be associated clinically with formation of depression in patients and hormones are known to mediate certain clinical manifestations of mood disorders. Chronic restraint stress induces a morphological reorganization of neurons in certain areas of rodent brain, effects that are also accompanied by behavioral changes. Although the precise mechanisms underlying these effects remain to be elucidated, a growing body of data suggests that alterations in neuroprotection and mitochondrial functions of glucocorticoid receptors may play an important role in regulating various forms of synaptic and neuronal plasticity;we have sought to investigate the mitochondrial functions regulated by steroid hormones during chronic stress. Glucocorticoids play an important biphasic role in modulating synaptic and neural events, with low doses enhancing synaptic and neuronal plasticity and chronic, higher doses producing inhibition. We undertook a series of experiments to elucidate the mechanisms underlying these biphasic effects. We found that 1) glucocorticoid receptors (GRs) formed a complex with the anti-apoptotic protein Bcl-2 in response to corticosterone treatment, and 2) translocated with Bcl-2 into mitochondria after acute treatment with low or high doses of corticosterone in primary cortical neurons. However, after three days of treatment, high but not low doses of corticosterone resulted in a decrease in GR and Bcl-2 levels in mitochondria. In addition, three independent measures of mitochondrial function, mitochondrial calcium holding capacity, mitochondrial oxidation, and membrane potential were also regulated by long-term corticosterone treatment in an inverted U-shape. This regulation of mitochondrial function by corticosterone correlated with neuroprotection: that is, treatment with low doses of corticosterone demonstrated a neuroprotective effect, whereas treatment with high doses enhanced kainic acid (KA, a neural toxin)-induced toxicity of cortical neurons. As with the in vitro studies, Bcl-2 levels in the mitochondria of the prefrontal cortex were significantly decreased, along with GR levels, after long-term treatment with high-dose corticosterone. These findings have the potential to contribute to a more complete understanding of the mechanisms by which glucocorticoids and chronic stress regulate cellular plasticity and resilience, and to inform the future development of improved therapeutic treatments. Recent studies focused on the molecular mechanism of the GR/Bcl-2 trafficking. BAG-1, a downstream target of lithium and valproate, interacts with PTSD- and depression-associated gene FKBP51, glucocorticoid receptors (GRs), Bcl-2, heat shock protein 70, and inhibits GR receptor nuclear translocation in response to corticosterone (CORT). We studied BAG-1 and FKBP51 levels in the mitochondria after CORT treatment. We found that BAG1 and FKBP51 distribution in the mitochondria was significantly increased in response to CORT treatment in cultured cortical neurons;interestingly, similar effects were seen with GR and Bcl-2 mitochondrial levels after CORT. Furthermore, FKBP51 formed a complex with BAG-1, and the formation of FKBP51 and BAG-1complex increased after CORT treatment. However, total BAG-1 protein expression was decreased in neuronal homogenates, suggesting a complex regulation by CORT. Notably, BAG-1 overexpression in BAG-1 transgenic mice not only blocked the reduction of GR/Bcl-2 in the mitochondria, but also the formation of anhedonic-like behavior after CORT treatment. Wild type FVB mice showed a reduction in saccharine consumption after CORT treatment;however, BAG-1 transgenic mice did not, suggesting a resilience to high dose CORT. These data suggest that the regulation of the trafficking of key plasticity molecules to the mitochondria may play an important role in the mechanisms by which chronic stress and glucocorticoids regulate cellular plasticity and resilience, and ultimately sensitivity/resilience to the development of stress-induced psychiatric disorders.