26 These age-dependent effects are

particularly of interest given a burgeoning literature describing the ability of reproductive steroids to regulate cell death and survival through effects on cell survival proteins (eg, Bcl-2, Bax), signal transduction (eg, MAPK, Akt), amyloid precursor protein metabolism, and free radical species generation.17,27-30 Effects on survival operate at both ends of the developmental spectrum. Early Inhibitors,research,lifescience,medical effects influence pruning31 and the shaping of brain circuitry. Modulation of neural and glial survival during aging provides yet another means by which reproductive steroids may influence the susceptibility to neuropsychiatrie illness, given the putative role of neurodegeneration in depression32-34 and its demonstrated role in Alzheimer’s disease. Environmental context The brain is a nonlinear transform system, in which the response to a stimulus can be altered as a function of past history or present environment. Multiple demonstrations of this process can be found in the animal literature. For example, behavioral sensitization refers to an DNA Damage inhibitor amplified Inhibitors,research,lifescience,medical behavioral response (eg, aggression) to repeated exposure to a pharmacologic stimulus.35 Two elements of this process are of further interest. First, Antelman has suggested that even without repeated administration, exposure to certain drugs may yield an amplified

response upon readministration, simply by virtue of the passage Inhibitors,research,lifescience,medical of time.36 There is a «memory” following exposure that alters the response when the stimulus is rc-prcscnted. Inhibitors,research,lifescience,medical Second, Post and coworkers have demonstrated that expression of behavioral sensitization may be

context dependent, in that the exaggerated response elicited to cocaine in the test cage will not be manifest if, after sensitization is achieved, the cocaine is administered in the home cage.37 Both past experience and environment, then, may alter subsequent response. One of the most impressive demonstrations of experience (and development )-related alterations in context is provided by the work of Meaney and coworkers. These authors38 expanded Inhibitors,research,lifescience,medical the work of Levine39 and showed that the separation and handling of rat pups elicited licking and grooming behavior from mothers that differentially and permanently determined the nature of the offspring’s response to stressors. Meaney and coworkers then went on to demonstrate in cross-fostering many studies that it was the maternal licking and grooming behavior, not the genetic factors, that influenced the licking and grooming behavior (as well as the stress responsivity) of the female offspring, and that the “adopted” licking and grooming behavior and stress responsivity were passed down to subsequent generations.40 This series of studies, then, demonstrates that maternal behavior can alter the developmental context, such that permanent and dramatic differences in response – from the transcriptional to the behavioral level – are programmed into the offspring.