The hippocampus is a vulnerable and yet resilient brain region, and excitatory amino acids play an important role in normal plasticity as well as in damage produced by ischemia, seizures and head trauma. Stress also has important effects on the hippocampus via adrenal steroids and excitatory amino acids. We found receptors for adrenal steroids in hippocampal neurons, and the actions of so-called "stress hormones" has been investigated with increasing intensity over the past several decades. The amygdala is another target of stress and shows structural plasticity in stress that is sometimes opposite to that seen in hippocampus - that is, when stress causes hippocampal neurons to retract it causes amygdala neurons to grow. Accompanying these changes are decreases in hippocampal-dependent memory functions and increases in fear and aggression that are related to the amygdala. There are also changes in neuronal excitability that are regulated acutely by adrenal steroids and chronically by repeated stress.

Besides dendritic remodeling, stress also influences the replacement of neurons in the dentate gyrus of the hippocampus. In the adult brain, proliferation of neural stem cells continues in the subventricular zone, providing new neurons for the olfactory bulb and the neocortex, and in the dentate gyrus. Proliferating precursor cells reside in the subgranular zone of the dentate gyrus. The newly born cells express markers of immature neurons and extend axonal processes toward the CA3 region of the hippocampus. As they differentiate, these cells express mature neuronal markers and begin to migrate into the granule cell layer. Neurogenesis and survival are regulated positively by growth factors and certain hormones such as IGF-1 and estrogens and negatively by glucocorticoids, excitatory amino acids and opioids.

Chronic restraint stress not only induces atrophy of apical dendrites in CA3 pyramidal neurons, it also suppresses neurogenesis. After 6 weeks it results in a 6% smaller dentate gyrus with 13% fewer granule neurons. Studies of fear conditioning show a specific suppression of neurogenesis associated with pairing of a tone and a shock.

Insulin plays a role in the structural responses of the brain to stressors. Lack of insulin causes a decrease in dentate gyrus neuron number and leads to increased remodeling of dendrites of CA3 neurons that is further accelerated by repeated restraint stress. There are two insulin-sensitive glucose transporters in the brain that appear to mediate at least some of the effects of insulin. Stress and hyperglycemia both increase oxidative stress in the brain and this is likely to contribute, over time, to impaired neural function in chronic stress and diabetes.

Another target of action of adrenal steroids is the mesolimbic and nigrostriatal dopamine systems and their associated neuropeptides. Adrenal steroids modulate the neuropeptides that, in turn, regulate dopaminergic activity and thus contribute to effects of stress on this important brain system. Studies of psychosocial stress in a dominance hierarchy have revealed long-lasting effects of subordination stress on dopaminergic function in the mesolimbic system that may be related to the potential for substance abuse.

McEwen, B.S., Sapolsky, R.M. Stress and cognitive function. Current Opinion in Neurobiology. 5:205- 216 (1995).

McEwen, B.S., Albeck, D., Cameron, H., Chao, H., Gould, E., Hastings, N., Kuroda, Y., Luine, V., Magarinos, A.M., McKittrick, C.R., Orchinik, M., Pavlides, C., Vaher, P., Watanabe, Y., Weiland, N. Stress and the Brain: A Paradoxical Role for Adrenal Steroids. Vitamins and Hormones 51:371-402 (1995).

McEwen, B.S. Stress and hippocampal plasticity. Ann. Rev. Neurosci. 22:105-122 (1999).

McEwen, B.S., de Leon, M.J., Lupien, S.J., and Meaney, M.J. Corticosteroids, the aging brain and cognition. TEM 10:92-96 (1999).

Conrad, C.D., Lupien, S.J., and McEwen, B.S. Support for a bimodal role for type II adrenal steroid receptors in spatial memory. Neurobiol. of Learning & Memory 72:39-46 (1999).

Lupien, S.J., Nair, N.P.V., Briere, S., Maheu, F., Tu, M.T., Lemay, M., McEwen, B.S., and Meaney, M.J. Increased cortisol levels and impaired cognition in human aging: Implication for depression and dementia in later life. Reviews in Neurosciences 10:117-139 (1999).

McEwen, B.S. The neurobiology of stress: from serendipity to clinical relevance. Brain Res. 886:172-189 (2000).

Pawlak, R., Magarinos, A.M., Melchor, J., McEwen, B., and Strickland, S. Tissue plasminogen activator in the amygdala is critical for stress-induced anxiety-like behavior. Nature Neurosci. 6:168-174 (2003).

MacQueen, G.M., Campbell, S., McEwen, B.S., Macdonald, K., Amano, S., Joffe, R.T.. Nahmias, C., and Young, L.T. Course of illness, hippocampal function, and hippocampal volume in major depression. Proc. Natl. Acad. Sci. USA 100:1387-1392 (2003).

Pham, K., Nacher, J., Hof, P.R., and McEwen, B.S. Repeated restraint suppresses neurogenesis and induces biphasic PSA-NCAM expression in the adult rat dentate gyrus. Eur. J. Neurosci. 17:1-8 (2003).