It has become increasingly clear that males and females differ even more dramatically than we previously thought. Not only do they exhibit differing responses to stress and environmental experience, but they can also respond in opposite directions. In rats, exposure to an acute stressful event enhances associative learning in males while dramatically impairing performance in females (Wood et al 2001, Wood &Shors 1998;Shors et al., 1998, 2002). These opposite effects of stress on memory formation are accompanied by similarly opposite effects on the presence of dendritic spines in the hippocampal formation (Shors et al 2001). Moreover, these opposite effects of stress are mediated by different hormonal systems between the sexes (Wood et al 2001, Beylin &Shors 2002). Sex differences usually arise from activational and organizational effects of sex hormones which fluctuate across the lifespan, especially in females. The experiments described in this competing continuation capitalize on hormonal fluctuations and changes in emotionality that occur during very early development, puberty, post-partum and menopause. They are designed to associate and dissociate changes in learning ability and responses to stressful experience with changes in hormones and density of dendritic spines in the hippocampal formation. Finally, experiments are designed to explore a potential relationship between sex differences in learning and the expression of growth hormone (GH) in the hippocampus, a gene that is preferentially induced by learning (Donahue et al., 2002). Techniques include trace eyeblink conditioning in the rat, Golgi impregnation and light microscope analysis, real-time polymerase chain reaction, in situ hybridization, radioimmunoassay, and surgical manipulation of glucocorticoids and ovarian hormones. Overall, these studies will identity the neuronal and hormonal mechanisms that underlie sex differences in learning and opposite responses to stressful experience in males versus females. Because mental disorders often emerge or are exacerbated during these life changes, the studies will provide insight into sex differences in mental illness, especially those experienced so frequently by women: post-traumatic stress disorder (PTSD), unipolar, post-partum and post-menopausal depression, as well as Alzheimer's disease.