The Molecular Cascade of Stress

by Kathleen M. Wong

Daniela Kaufer studies the effects of stress on the brain. Credit: Alon Friedman

UC Berkeley biologist Daniela Kaufer investigates how the body transforms the psychological signal of stress into physiological changes to the brain. Her research demonstrates that stress affects every level of functioning, from how genes are transcribed to what proteins are translated. These tiny but profound shifts ultimately alter how entire body systems perform.

Kaufer's interest in stress began as a graduate student at the Hebrew University in Jerusalem, Israel, in the Soreq lab. One of her collaborators, neurosurgeon Alon Friedman of Ben-Gurion University, was investigating the origins of Gulf War syndrome. The symptoms appeared consistent with neurological damage, though no nerve gas was used during the war.

Kaufer and Friedman found that stress opens temporary leaks in the blood-brain barrier, the membrane separating the circulatory system from the central nervous system. "It's a very dynamic structure; it's not at all a barrier in the sense you think of it," Kaufer says. "The fact that the barrier is open brings into the brain a lot of things that shouldn't be there."

During short-term stress, opening the membrane's junctions can be advantageous. "The organism can focus as much as possible on shuttling energy to the places that need it most, which means sending lots of glucose to the muscles and brain," she says. But among Gulf War soldiers, battle stress may have allowed anti-nerve gas agents or other toxic substances such as pesticides to contact and injure the brain.

Kaufer's research is providing a molecular explanation for why exposure to stress affects the growth and behavior of brain neurons. Here, a molecule of corticosterone, a principal stress hormone, is shown against a background of cultured rat neurons. Credit: Eyal Soreq

An epileptic seizure is an electrical storm in the brain. Instead of firing in a smooth and coordinated manner, the neurons generate bursts of erratic electrical impulses. The scientists found they could trigger these neural storms by exposing slices of rat brain to a common blood protein called serum albumin.

The scientists figured the albumin was binding directly to neurons. But further experiments proved them wrong. Albumin labeled with fluorescent markers wound up not in neurons but in brain cells called astrocytes.

Astrocytes are the brain's chemical custodians. They buffer the concentration of ions around neurons, which affects how easily neurons will fire. Kaufer and colleagues noticed that potassium levels were abnormally high in rat brains exposed to albumin. They also found that astrocytes exposed to albumin had abnormally few potassium channels. The implication: albumin disrupts potassium channel production in astrocytes.

Further experiments revealed that astrocytes use a specific receptor to take up albumin. Blocking that receptor, the researchers found, protects rat brains exposed to albumin from becoming epileptic. Kaufer is now figuring out which genes turn on and off during the development of epilepsy. At the same time, she is seeking small molecules to block this cascade and prevent trauma-induced epilepsy altogether.

Kaufer is pursuing two additional avenues of research into the molecular underpinnings of stress. One is how stress prevents new neuron production in the brain. The answers could explain why people often draw a blank when recalling extremely traumatic events. With gene therapy, she can create cells that no longer react to glucocorticoids, and therefore can't tell the body is experiencing stress. "I can put these genes in stem cells or newborn neurons or mature neurons and ask, does this change memory ability in mice?" Kaufer says.

Kaufer is also discovering that cells fine-tune their machinery to produce proteins better adapted to stressful conditions. Instead of transcribing entirely different suites of genes, she's found, cells splice existing protein templates in new ways. "The groups of proteins that are changing dictate where the cutting and ligating occurs during splicing," Kaufer says

Kaufer hopes her work will lead to ways of inoculating the body against the most damaging forms of stress. "If I'm right, and cells have good means of dealing with stressful situations, then by uncovering these mechanisms we can tap into that resource, and design therapeutic tools that use the body's own plastic capabilities. Eventually maybe before you send somebody into a stressful situation like war, you might be able to better prepare their brains to deal with stress so that they will be less likely to develop post-traumatic stress disorder at the end of it."

Source / Credit: University of California, Berkeley