Cell morphology Early studies of cell morphology found that repeated stress causes atrophy of CA3 pyramidal neurons in the hippocampus, characterized by a decreased number and length of apical dendrites.29,30 More recent studies have shown that pyramidal neurons in the PFC undergo a similar retraction/atrophy of apical dendrites, and a reduction in spine number in response to immobilization stress (Figure 2). 31 Chronic exposure to high levels of exogenous corticosterone, the rodent equivalent of Cortisol, causes a Inhibitors,research,lifescience,medical similar atrophy of hippocampal and PFC neurons.32,33 In contrast to most neurological disorders, in which the structural alterations

and loss of neurons is permanent, the stress-induced atrophy of hippocampal and PFC neurons is SGC-CBP30 nmr reversible. Most notably, removing animals from stress normalizes the dendritic arborization of pyramidal neurons over a period of several weeks.3,32,34 Moreover, chronic administration of certain antidepressants blocks or reverses hippocampal atrophy, Inhibitors,research,lifescience,medical even with continued stress exposure.29,30 This reversibility supports the notion that dendritic alterations represent a type of structural plasticity that has functional consequences. Cell proliferation Inhibitors,research,lifescience,medical In addition to dendritic atrophy, chronic stress decreases the proliferation

of new cells in the adult hippocampus Inhibitors,research,lifescience,medical and PFC. The dentate gyrus of the hippocampus is one of the few regions of the brain that continues to give rise to new neurons in adulthood, in rodents as well as nonhuman primates and humans.35,36 Interestingly, the rate of neurogenesis is influenced by environmental and endocrine factors, and stress is one of the most consistent and robust negative regulators (Figure 2). The proliferation of new neurons is decreased by different types of stress, including restraint, footshock, maternal separation, predator

odor, Inhibitors,research,lifescience,medical psychosocial stress, and sleep deprivation, and by administration of exogenous corticosterone.37 In the PFC the proliferation of glia is decreased by exposure to repeated stress38 or corticosterone treatment.39 Chronic stress also decreases the no number of glial fibrillary acidic protein (GFAP)-positive astrocytes in the hippocampus.40 In contrast, antidepressants increase the proliferation of neurons and glia in the hippocampus and/or PFC, and block or reverse the effects of stress.37,38,41,42 These effects require chronic administration (weeks), consistent with the time course for the therapeutic response to antidepressants. Different classes of antidepressant increase cell proliferation in rats, including serotonin selective transporter inhibitors, norepinephrine selective reuptake inhibitors (NSRIs), and electroconvulsive seizures (ECS),41,43,44 indicating that this is a common target of ADT.