Discovering a Biologic Basis for the Neuropsychiatric Effects of Stress

McEwen, Bruce

At a time when most scientists studying the brain focused on ion movements and chemical neurotransmission, Bruce McEwen (1938- ) wanted to understand how hormones regulate brain function and behavior by regulating genes in the brain. Conventional wisdom held that the brain was insulated from the effects of hormones, except for the hypothalamus, and that hormones acted rapidly, like neurotransmitters. But McEwen knew that certain steroid hormones—for example, the stress-response hormone, cortisol—could turn on genes in other parts of the body. And in 1968 he discovered how these hormones act in the brain but not just on the hypothalamus: he found receptors for adrenal steroids in the hippocampus of rats, and, later, rhesus monkeys.

This discovery opened the door to a new understanding of how adrenal steroids and other hormones impact human mental health. The hippocampus, an area of the brain where memories related to recent events and spatial orientation are formed, is sensitive to degeneration in dementia, and vulnerable to seizures and stroke. Studies in McEwen’s laboratory have shown that stress hormones alter the structure of hippocampal neurons. In the process, the McEwen lab found that the dentate gyrus region of the hippocampus continues to produce new neurons throughout adult life. These basic findings led to the discovery by other investigators that the hippocampus becomes smaller in depressive illness, posttraumatic stress disorder, Cushing’s disease, and Alzheimer’s disease.

The work in McEwen’s laboratory also launched a new aspect of neuroendocrinology, at the intersection of neurobiology, endocrinology, and behavioral science. Many of McEwen’s students and postdoctoral fellows have made groundbreaking discoveries and gone on to become leaders in this field. These contributions include elucidating the damaging role of adrenal steroids in aging, finding that new nerve cells are generated in the dentate gyrus in adult mammals, and defining the key role of early life experiences in shaping brain function.

Further basic studies in the McEwen laboratory have provided a foundation for the emerging scientific view of the adult brain as malleable not only by stress and stress hormones but also by sex hormones. A breakthrough on the sex hormone front came in 1990 when McEwen and Catherine Woolley discovered that ovarian hormones regulate formation of connections (synapses) between nerve cells in an unexpected part of the brain - the hippocampus, where certain types of memories are formed. The second breakthrough came in 2001, when McEwen, Steven Alves and Teresa Milner from the Weill Cornell Medical College, discovered receptors for estradiol (the dominant form of estrogen in the blood of premenopausal women) in the hippocampus. Using high resolution electron microscopy, they demonstrated estrogen receptors in the synapses, where chemical neurotransmission occurs. These findings launched a series of investigations in McEwen's Rockefeller laboratory that have revised scientific dogma, contributing to a new view that many regions of the adult brain are extremely responsive to circulating hormones, and in particular the idea that sex hormones influence the whole brain, not just those regions concerned with reproduction.

Under severe and persistent stress, cortisol secretion can rise above normal and this may cause a variety of damaging effects on the body. Medical illustrator: Lydia Kibiuk

McEwen has, in addition, developed a new definition of how the body and brain are affected by chronic stress: allostatic load, the wear and tear caused by chronic stress and stress-related lifestyles, which lead to disease. The term is based on the word “allostasis”, meaning the beneficial ways in which the brain and body adapt to acute stress using hormones and other chemical mediators. Thus, allostatic load highlights how the protective effects of mediators of stress can also cause disease. These concepts are providing a biological basis for new approaches to public health and epidemiology. Through McEwen’s activity in the MacArthur Foundation Research Network on Socioeconomic Status and Health and the National Council on the Developing Child, these concepts are providing a biological underpinning for new approaches to understanding and treating the growing problem of stress in human society.

Bruce S. McEwen received his bachelor’s degree from Oberlin College in 1959, and his PhD from The Rockefeller University in 1964. He was a U.S. Public Health Service Postdoctoral Fellow at the Institute of Neurobiology in Goteborg, Sweden from 1964 to 1965, then assistant professor in zoology at the University of Minnesota, and returned to Rockefeller in 1966 as assistant professor. He was appointed associate professor in 1971, and professor and head of lab in 1981; he was named Alfred E. Mirsky Professor in 1999. McEwen is a past president of the Society for Neuroscience and a member of the U.S. National Academy of Sciences, the American Academy of Arts and Sciences, and the Institute of Medicine. His work has been recognized with the Dale Medal of the British Endocrine Society (2001), the Goldman-Rakic Prize for Cognitive Neuroscience (2005) from the National Alliance for Research for Schizophrenia and Depression, the Karl Lashley Award from the American Philosophical Society (2005), the Pasarow Award in Psychiatry (2006) and the Gold Medal of the Society of Biological Psychiatry (2009).

Selected Publications

McEwen BS, Weiss J, and Schwartz L. Selective retention of corticosterone by limbic structures in rat brain. Nature, 1968, 220: 911-912

Zigmond, R.E. and McEwen, B.S. Selective retention of oestradiol by cell nuclei in specific brain regions of the ovariectomized rats.  J. Neurochem. 17:889-899 (1970).

Gerlach J and McEwen BS. Rat brain binds adrenal steroid hormone: radioautography of hippocampus with corticosterone. Science, 1972, 175: 1133-1136

Denef, C., Magnus, C. and McEwen, B.S. Sex differences and hormonal control of testosterone metabolism in rat pituitary and brain.  J. Endocr. 59:605-621 (1973).

DeKloet, R., Wallach, G. and McEwen, B.S. Differences in corticosterone and dexamethasone binding to rat brain and pituitary.  Endocrinology 96:598-609 (1975).

MacLusky, N and McEwen, B.S. Oestrogen modulates progestin receptor concentrations in some rat brain regions but not in others.  Nature 274:276-278 (1978).

Luine, V.N., Park, D., Joh, T., Reis, D. and McEwen, B.S. Immunochemical demonstration of increased choline acetyltransferase concentration in rat preoptic area after estradiol administration.  Brain Res 191:273-277 (1980).

Meaney M, Stewart J, Poulin P, and McEwen BS. The sexual differentiation of social play in Norway rat pups is mediated by the neonatal androgen-receptor system. Neuroendocrinology, 1983, 37: 85-90

Meaney M, Sapolsky RM, and McEwen BS. The development of the glucocorticoid receptor system in the rat limbic brain. I. Ontogeny and autoregulation. Brain Res, 1985, 18: 159-164

Sapolsky RM, Krey LC, and McEwen BS. The neuroendocrinology of stress and aging: The glucocorticoid cascade hypothesis. Endocr Rev, 1986, 7:284-301

Brinton, R. and McEwen, B.S. Vasopressin neuromodulation in the hippocampus. J. Neurosci. 9:752-759 (1989).

Gould E, Woolley C, and McEwen BS. Short-term glucocorticoid manipulations affect neuronal morphology and survival in the adult dentate gyrus. Neuroscience, 1990, 37: 367-375

Woolley, C., Gould, E., Frankfurt, M. and McEwen, B.S. Naturally occurring fluctuation in dendritic spine density on adult hippocampal pyramidal neurons. J. Neurosci. 10:4035-4039 (1990).

Cameron H, Woolley C, McEwen BS, and Gould E. Differentiation of newly born neurons and glia in the dentate gyrus of the adult rat. Neuroscience, 1993, 56: 337-344

Cameron HA, McEwen BS, and Gould E. Regulation of adult neurogenesis by excitatory input and NMDA receptor activation in the dentate gyrus. J Neurosci, 1995, 15: 4687-4692

McKittrick, C., Blanchard, C., Blanchard, R., McEwen, B.S., and Sakai, R. Serotonin receptor binding in a colony model of chronic social stress. Biol. Psych. 37:383-393 (1995).

Lupien SJ, de Leon M, de Santi S, Convit A, Tarshish C, Nair NPV, Thakur M, McEwen BS, Hauger RL, and Meaney MJ. Cortisol levels during human aging predict hippocampal atrophy and memory deficits. Nature Neurosci, 1998, 1: 69-73

Milner TA, McEwen BS, Hayashi S, Li CJ, Reagan LP, and Alves SE. Ultrastructural evidence that hippocampal alpha estrogen receptors are located at extranuclear sites. J Comp Neurol, 2001, 429: 355-371

Seeman TE, McEwen BS, Rowe JW, and Singer BH. Allostatic load as a marker of cumulative biological risk: MacArthur studies of successful aging. Proc Natl Acad Sci USA, 2001, 98: 4770-4775

Akers KG, Yang Z, DelVecchio DP, Reeb BC, Romeo RD, McEwen BS, and Tang AC. Social competitiveness and plasticity of neuroendocrine function in old age: Influence of neonatal novelty exposure and maternal care reliability. PLoS ONE, 2008, 3(7):e2840

Bulloch, K., Miller, M.M., Gal-Toth, J., Milner, T.A., Gottfried-Blackmore, A., Waters, E.M., Kaunzner, U.W., Liu, K., Lindquist, R., Nussenzweig, M.C., Steinman, R.M., and McEwen, B.S. CD11c/EYFP transgene illuminates a discrete network of dendritic cells within the embryonic, neonatal, adult, and injured mouse brain. J. Comp. Neurol. 508:687-710 (2008).

Milner, T.A., Lubbers, L.S., Alves, S.E., and McEwen, B.S. Nuclear and extranuclear estrogen binding sites in the rat forebrain and autonomic medullary areas. Endocrinology 149:3306-3312 (2008).
PMC: 2453087

Maeng, S., Hunsberger, J.G., Pearson, B., Yuan, P., Wang, Y., Wei, Y., McCammon, J., Schloesser, R.J., Zhou, R., Du, J., Chen, G., McEwen, B., Reed, J.C., and Manji, H.K. BAG1 plays a critical role in regulating recovery from both manic-like and depression-like behavioral impairments. Proc. Natl. Acad. Sci. USA 105:8766-8771 (2008).
PMC: 2430919

Spencer, J.L., Waters, E.M., Milner, T.A., and McEwen, B.S. Estrous cycle regulates activation of hippocampal Akt, LIM kinase, and neurotrophin receptors in C57BL/6 mice. Neuroscience 155:1106-1119 (2008).
PMC: 2621322

Waters, E.M., Torres-Revon, A.T., McEwen, B.S., and Milner, T.A. Ultrastructural localization of extranuclear progestin receptors in the rat hippocampal formation. J. Comp. Neurol. 511:34-46 (2008).
PMC: 2577145

Liston, C., McEwen, B.S. and Casey, B.J. Psychosocial stress reversibly disrupts prefrontal processing and attentional control. Proc. Natl. Acad. Sci. USA 106:912-917 (2009).
PMC: 2621252

Shansky, R.M., Hamo, C., Hof, P.R., McEwen, B.S., and Morrison, J.H. Stress-induced dendritic remodeling in the prefrontal cortex is circuit specific. Cerebral Cortex  19:2479-2484 (2009).
PMC: 2742599

Hunter, R.G., Bellani, R., Bloss, E., Costa, A., McCarthy, K., and McEwen, B.S. Regulation of kainate receptor subunit mRNA by stress and corticosteroids in the rat hippocampus.  PLoS One 4:E4328 (2009).
PMC: 2627898

Du, J., Wang, Y., Hunter, R., Wei, Y., Blumenthal, R., Falke, C., Khairova, R., Zhou, R., Yuan, P., Machado-Vieira, R., McEwen, B.S., and Manji, H.K. Dynamic regulation of mitochondrial function by glucocorticoids. Proc. Natl. Acad. Sci. USA 106:3543-3548 (2009).
PMC: 2637276

Hill, M.N. and McEwen, B.S. Endocannabinoids: The silent partner of glucocorticoids in the synapse. Proc. Natl. Acad. Sci. USA 106:4579-4580 (2009).
PMC: 2660761

Hill, M.N., Hunter, R.G., and McEwen, B.S. Chronic stress differentially regulates cannabinoid CB1 receptor binding in distinct hippocampal subfields. Eur. J. Pharmacol. 614:66-69 (2009).
PMC: 2746437

Goldwater, D.S., Pavlides, C., Hunter, R.G., Bloss, E.B., Hof, P.R., McEwen, B.S., and Morrison, J.H. Structural and functional alterations to rat medial prefrontal cortex following chronic restraint stress and recovery. Neuroscience 164:798-808 (2009).
PMC: 2762025

Further Reading

McEwen BS. Stress and hippocampal plasticity. Annu Rev Neurosci, 1999, 22: 105-122

McEwen BS. Protective and damaging effects of stress mediators. N Engl J Med, 1998, 338: 171-179

Adler NE, Marmot M, McEwen BS, and Stewart J (eds.). Socioeconomic Status and Health in Industrial Nations: Social, Psychological, and Biological Pathways. Annals NY Acad Sci, 1999, vol 896

McEwen BS. Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol Rev, 2007, 87: 873-904

McEwen BS and Milner TA. Hippocampal formation: Shedding light on the influence of sex and stress on the brain. Brain Res Rev, 2007, 343-355

Roozendaal, B., McEwen, B.S. and Chattarji, S. Stress, memory and the amygdala. Nature Rev. Neurosci. 10:423-433 (2009).

Lupien, S.J., McEwen, B.S., Gunnar, M.R. and Heim, C. Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat. Rev. Neurosci. 10:434-445 (2009).

Shonkoff, J.P., Boyce, W.T., and McEwen, B.S. Neuroscience, molecular biology, and the childhood roots of health disparities. JAMA 301:2252-2259 (2009).

McEwen BS. The Hostage Brain. New York: Rockefeller Univ Press, 1994

McEwen BS. The End of Stress As We Know It. Washington, DC: National Academies Press, 2002

Shonkoff, J.P., Boyce, W.T., and McEwen, B.S. Neuroscience, molecular biology, and the childhood roots of health disparities. JAMA 301:2252-2259 (2009).


Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology at Rockefeller University

A Conversation with Bruce McEwen

MacArthur Foundation Network on Socioeconomic Status and Health

National Scientific Council on the Developing Child

Leaders in Neuroendocrinology from the McEwen Laboratory

Roberta Brinton (postdoc; years at RU – 1984-1988)

Heather Cameron (student; years at RU – 1990-1995)

E.R. deKloet (postdoc; years at RU – 1973-1975)

Carl Denef (postdoc; years at RU – 1971-1973)

Elizabeth Gould (postdoc; years at RU – 1992-1996)

Victoria Luine (postdoc; years at RU – 1972-1975)

Sonia Lupien (postdoc: years at RU – 1995-1996)

Neil MacLusky (postdoc; years at RU – 1974-1978)

Michael Meaney (postdoc; years at RU – 1981-1983)

Randall Sakai (postdoc: years at RU – 1988-1991)

Robert Sapolsky (student; years at RU – 1979-1984)

Catherine Woolley (student; years at RU – 1987-1993)

Richard Zigmond (student; years at RU – 1966-1971)