Too Much Stress Damages The Brain

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International Congress of NeuroEndocrinology
Report: Investigator: Bruce McEwen

by Julie Clayton

Bruce McEwen who directs the Laboratory of Neuroendocrinology at Rockefeller University in New York today reported that, in addition to causing overall shrinkage of the rat hippocampus and reductions in the neuronal processes called dendrites, stress also blocks neurogenesis.

His team has found reduced proliferation of neuronal precursor cells in the rat hippocampus following three weeks of a chronic daily form of stress known as restraint stress. They found the effect in the dentate gyrus region, the region where McEwen's long-time collaborator Elizabeth Gould of Princeton University first discovered that neurogenesis occurs normally throughout life. The survival of the cells was "cut in half," said McEwen. The total number of granule cells was reduced by 13% and the volume of the region reduced by 6%.

The dentate gyrus is known to be particularly important in forming memories of sequences of events. McEwen's team also saw the same effect in the CA1 region of the hippocampus. These studies add to a picture already emerging from McEwen's previous work showing that stress causes dendrite remodeling and a decrease in neuronal number in the CA3 region of the hippocampus, to which the dentate gyrus projects.

Glucocorticoids, released by the adrenals during stress, appear to be key mediators of the reduction in cell turnover and number. Administering glucocorticoids alone, in the absence of stress stimuli, produces the same result. The extracellular release of excitatory amino acids such as glutamate also appears to play a role, as does the sustained intracellular activation of the signalling molecule CREB, reported McEwen. He suggested that blocking neurogenesis may be a form of protection against damage from over-excitation.

On a positive note, McEwen revealed that within 7-10 days of removing the stress stimulus, neurogenesis was restored to its full capacity. It remains to be seen, however, whether the effects of a more prolonged period of stress - 6 weeks in the rats - are similarly reversible.

Nonetheless, says McEwen, the 3-week data raises the possibility that damage that may occur as a result of similar processes in the brains of patients with depression may in fact be reversible. Magnetic resonance imaging (MRI) studies of patients who have repeated episodes of major depression have revealed shrinkage of the hippocampus that continues despite standard anti-depressant treatments. While the underlying mechanisms remain a mystery, they may involve a similar dendrite remodeling, loss of cell number, and failure of neurogenesis. Indeed, depression is known to involve excessive activity of the stress hormone system, with increased levels of glucocorticoid hormones that mediate these effects.

Even for patients who feel better following anti-depressant medication, warned McEwen: "We have to seek out a new set of drugs because our brains may still be falling apart."

McEwen's team has already identified beneficial effects - at least for rats - of the anti-seizure drug tianeptine, which can prevent the experimentally stress-induced remodeling of dendrites. But this is not used clinically as an anti- depressant.