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Throughout life, hormones alter behavior and mood, regulate neuroendocrine activity, protect the brain from stress, and regulate brain aging and certain disease processes. McEwen’s laboratory takes an interdisciplinary approach to investigate how stress and sex hormones act on the brain. His work has wide-ranging implications for understanding how the brain changes from embryonic development through adult life.

The neuroendocrine system links behavior and experience with hormone secretion. Hormones, in turn, regulate body functions such as reproduction, fluid and mineral balance, metabolism, and immune activity. They also help shape the developing brain, affect mood and behavior, and contribute to aging and disease.

In studying the cellular and molecular mechanisms underlying the effects of stress and sex hormones on the hippocampus and other regions of the adult or developing brain, the McEwen laboratory has helped create a new understanding of how the brain changes in adult life and in development. Their work has implications for understanding the impact of stress on the brain and sex differences in human brain function as well as in Alzheimer’s disease, depression, posttraumatic stress disorder, and normal aging.

In relation to stress, the McEwen lab has shown that hormone actions on structural plasticity are intertwined with the actions of excitatory amino acid transmitters, NMDA receptors, other neurotransmitters, and BDNF. McEwen has also found that chronic stress reduces the number of neurons in the dentate gyrus. In the hippocampus, the lab has shown that chronic stress causes neurons to undergo remodeling of dendrites, and excitatory amino acids are important regulators of this neuronal remodeling, acting in concert with glucocorticoids. Stress-induced remodeling is largely reversed once the stress is removed, although gene expression patterns continually change with experience and resilience declines with aging.

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. The McEwen lab has recently shown that age-related impairment of cognitive function can be reduced by treatment with riluzole, a drug that reduces glutamate overflow.

In studying the action of sex hormones, the researchers have identified sex hormone receptors in the hippocampus that regulate signaling pathways associated with synapse formation and maturation. 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 neuroprotective effects in the hippocampus and other brain regions.

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, self-regulation, and extinction of fear learning. In animals, aging leads to loss of the ability to promptly extend dendrites of the prefrontal cortex after cessation of stress.

Work conducted as part of the Neuroimmune-Physiology Program, headed by Karen Bulloch, has led to the discovery of dendritic-like cells in the brain that are activated by interferon-γ to present antigens. These cells increase in number in the aging brain, and are induced by viral infections and simulated stroke.