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Vol. LXI, No. 6
March 20, 2009

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Sapolsky Explores Stress from Uncommon Angle

Dr. Robert Sapolsky

Dr. Robert Sapolsky, guest lecturer for the NIMH Director’s Innovation Series

What do suicidal rats, beached whales, car crashes and schizophrenia have in common? The answer may help researchers solve the mysteries behind humankind’s habit of “spending 70 or 80 years of our lives having our bodies slowly go to hell on us,” according to Dr. Robert Sapolsky, who was featured Feb. 26 as a guest lecturer for the NIMH Director’s Innovation Series.

Sapolsky began by reviewing decades of research on how stress affects the body and brain. Though such processes were initially adaptive to a mammal’s survival in the wild, domesticated humans have evolved the ability to experience stress reactions in response to purely psychological situations, such as speaking in public or taking a test. Unlike a gazelle running for its life, in which case the life-saving stress response dissipates once the threat is gone, humans experiencing recurrent psychological stress expose themselves to chronically off-kilter body chemistry. This, in turn, can increase their vulnerability to anxiety, depression and other mental illnesses.

The Sapolsky lab’s research involves designing viral vectors that can deliver gene therapies into the brain to treat stress-related illnesses that arise from an excess of glucocorticoids. Glucocorticoids are hormones that are essential for converting food into energy and also play a key role in the body’s response to stress, among other functions. While the Sapolsky lab’s work is cutting-edge in the realm of human scientific understanding, it turns out that a primitive, single-celled parasite is at least one step ahead of the humans.

Enter Toxoplasma gondii.

The peculiar lifecycle of this protozoan involves a sophisticated hijacking of fear centers in a rat’s brain. Cats are the primary hosts for Toxoplasma, but during its life cycle, the organism infects a secondary host, usually rats. It must return to its primary host to reproduce, but nature dictates that rats avoid cats. What’s a parasite to do?

Toxoplasma effectively reprograms a rat’s brain, disconnecting key circuits in the amygdala, an area involved in fear and emotional learning. These rats lose their aversion to cat pheromones, but retain other natural fears, such as of bright lights and open spaces. Toxoplasma-infected rats do not experience proper stress reactions that would help ensure their survival when faced with a cat. Rather, in perhaps the most amazing behavioral feat of Toxoplasma, the re-programmed rats find cat pheromones to be attractive, even sexy. Cats then follow their natural instincts, consuming their prey and allowing the Toxoplasma to reach its primary host, where it continues the life cycle.

What does this have to do with beached whales, car crashes and schizophrenia? Sapolsky and other researchers have found that the Toxoplasma genome includes a gene that can induce a host’s brain to create dopamine, the neurotransmitter most closely linked with feelings of pleasure or reward. The combined effects of reduced fear and stress and increased hedonism may account for a variety of behavioral abnormalities in rats as well as other mammals.

For example, Sapolsky confirmed that Toxoplasma has been found in beached whales, dolphins and other marine life gone astray. Exposure to the parasite may also explain the case of sea otters in California that showed an increased risk of death by shark attacks. It’s possible that the infected otters were unable to escape effectively, or they may have behaved erratically and attracted extra attention from predators. Similarly, though the phenomenon bears further research, two independently conducted studies reported that Toxoplasma-infected humans were more likely to be in a traffic accident than non-infected people are. Since the basic structure of the brain is very similar among mammals, perhaps the same mechanism that attracts rats to cats may account for whales developing an urge to sunbathe, sea otters approaching sharks more closely than they should or humans being less cautious behind the wheel.

The connection between the parasite and schizophrenia may be even more subtle. Elevated levels of dopamine are a hallmark characteristic of schizophrenia, and some studies show that people with schizophrenia had a higher-than-chance rate of exposure to Toxoplasma as a fetus or in early childhood. Similarly, medications currently used to treat schizophrenia, which generally work by reducing dopamine activity, are as effective at reducing Toxoplasma-related behavior changes in rats as normal antibiotic treatments for the infection.

Understanding the nearly surgical precision of Toxoplasma infection and its control over different brain regions could radically change how we treat stress-related illnesses and many mental disorders. Sapolsky demonstrated that moving past our own scientific hubris and acknowledging that perhaps we do have something to learn about neurobiology from parasites may be the most innovative thinking of all.

The next NIMH Director’s Innovation Series lecture will be held on Mar. 26 from 3 to 4 p.m. in Conf. Rms. C & D at the Neuroscience Center, 6001 Executive Blvd. Dr. Gene Robinson of the Institute for Genomic Biology, University of Illinois at Urbana-Champaign, will speak on recent research that uses honeybees to explore the relationship between genes and social behavior. NIHRecord Icon

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