Long-term stress, like the kind that occurs when someone cares for a chronically ill parent or spouse, can impair short-term memory.

Researchers believe that this occurs because constant stress affects an area of the brain necessary for learning and memory, and the underlying mechanisms for this may also be to blame in more serious ailments, such as post-traumatic stress disorder (PTSD) and severe depression.

Rockefeller University scientists are inching closer to understanding exactly what these mechanisms are, and in a paper published this month in PNAS they expose one piece of the puzzle: An animal’s response to stress is at least partially dependent on an enzyme called tissue plasminogen activator, or tPA.

The hippocampus is a structure in the brain that’s responsible for episodic and contextual memory, those recollections that

involve people, places, and events. But two collaborating Rockefeller labs have found that chronic stress alters the neurons in an animal’s hippocampus - a finding that begins to explain the molecular mechanisms underlying stress-related memory impairment. Research by Sidney Strickland, head of the Laboratory of Neurobiology and Genetics, Bruce McEwen, Alfred E. Mirsky Professor and head of the Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, and their colleagues, shows that daily stress causes those hippocampal neurons to experience a decrease in the number of both their dendritic spines and NMDA receptors, two structures that play an important role in memory and dictate the strength of neuronal connection.

Two research associates in Strickland’s lab, Robert Pawlak and Jerry Melchor, placed unstressed mice in a water maze - a test designed to assess how well they could locate a hidden platform, and how long it took them to learn and remember its location. They then compared their performance to mice in which they had induced chronic stress by subjecting them to six hours of restricted motion every day for three weeks.

They found that the stressed mice were much slower to learn where the platform was located, but once they had figured it out they were just as good at remembering the location as the unstressed mice. “Stress fuzzes your brain because it slows down the cognitive process - the animal still gets to the same point if you train it long enough, but it’s slower,” McEwen says.

In order to assess whether tPA is required for a stress reponse, the researchers then repeated the experiment using mice bred to lack tPA, and found no difference in learning speed between the stressed and unstressed tPA-deficient mice. The results suggest that tPA somehow prevents damage to hippocampal neurons during times of stress, and an examination of the neurons - performed in collaboration with their colleagues in India - bore this out: Normal mice experienced a decrease in dendritic spines and NMDA receptors when they were stressed, while tPA-deficient rodents showed no change at all. And after ten stress-free days, the normal mice had already partially recovered. “This is consistent with our previous work that the effects of stress are reversible,” McEwen says. “Everything we’ve found out about stress and the hippocampus is that the effects are largely reversible if you terminate the stress.”

Strickland and McEwen believe that the decrease in dendritic spines is a protective mechanism. “We believe that these changes in the brain are actually protecting the hippocampus against more permanent damage. You’re still able to learn, but it slows you down,” McEwen says. In a typical brain, the hippocampus works in conjunction with another structure in the brain, the amygdala, to connect memory with emotion. So understanding how the normal hippocampus reacts to stress will allow researchers to better understand how a disconnect occurs in disorders like PTSD. “PTSD involves flashback memories that are not necessarily associated with real events. This could be due to a sensitization of the amygdala mechanism, and a disconnection from the real world of where you were and what you were doing,” McEwen says. “For a number of psychiatric illnesses, what goes on in the hippocampus and the amygdala, how they work together, and how they could be disconnected form one another by stressful events is all very interesting.”

Proceedings of the National Academy of Sciences: December 5, 2005

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