Throughout life, hormones alter behavior and mood, regulate neuroendocrine activity, protect the brain from stress and regulate brain aging and certain disease processes. Dr. McEwen’s laboratory studies how stress and sex hormones act on the brain, taking an interdisciplinary approach that combines behavioral analysis and measurements of hormone levels with neurochemical, morphological, neuropharmacological, cellular and molecular methodologies and collaborative translational studies. The neuroendocrine system links behavior and experience with hormone secretion. In turn, hormones regulate functions such as reproduction, fluid and mineral intake and balance, metabolism and immune activity. They also help shape the developing brain, affect mood and behavior and contribute to aging and disease. Dr. McEwen studies the cellular and molecular mechanisms underlying the effects of stress and sex hormones on neurogenesis, synaptogenesis and dendritic remodeling in the hippocampal region of the adult and developing brain. The hippocampus is involved in the formation of episodic, spatial and contextual memories and is one of the first brain structures to degenerate in Alzheimer’s disease. In relation to sex hormone action, the McEwen lab has identified sex hormone receptors in the hippocampus that regulate signaling pathways associated with synapse formation and maturation involving regulation of protein synthesis, neurotransmitter release and cytoskeletal remodeling. These “nongenomic” forms of the classical sex hormone receptors work in concert with the more classical genomic actions of sex hormones on gene expression, and they increase excitatory synapse formation and exert antiseizure and neuroprotective effects in hippocampus and other brain regions. In relation to stress, the McEwen lab has found that hormone actions on structural plasticity are intertwined with the actions of excitatory amino acid transmitters, kainate receptors, serotonin, GABA, other neurotransmitters and BDNF. Dr. McEwen has found that, in the dentate gyrus, chronic stress reduces neuron number and contributes to cognitive impairment. In the hippocampus, chronic stress causes neurons to undergo remodeling of dendrites. Excitatory amino acids — in particular, NMDA receptors — are important regulators of neuronal remodeling, acting in concert with glucocorticoids. The lab has also shown that the stress-induced remodeling is largely reversed once the stress is removed. The McEwen lab has recently expanded its scope of study to investigate stress-induced structural remodeling in the amygdala, which is involved in fear and strong emotions, and the prefrontal cortex, which is involved in working memory, decision making and extinction of fear learning. Recent work has found, in humans, an effect of chronic perceived stress on mental flexibility and functional activity in the prefrontal cortex that is analogous to animal studies. In animals, aging leads to loss of the ability to promptly extend dendrites of the prefrontal cortex after cessation of stress. Work by the neuroimmune-physiology group, headed by Karen Bulloch, has revealed important cell types characteristic of the immune system, namely brain dendritic cells, that are present in the normal, undamaged brain, accumulate in the aging brain and are activated in response to simulated stroke and interferon-γ. The group is working to characterize their functions. The McEwen laboratory has helped create a new understanding of how the brain changes in adult life and in development, with implications for understanding the impact of stress on the brain and sex differences in human brain function, abnormalities, Alzheimer’s disease, depression, posttraumatic stress disorder and aging.