According to the National Institute of Mental Health, roughly 19 million people in the United States have mental illnesses that involve persistent, outsized fear responses to seemingly ordinary stimuli. A door slam becomes a gun's report to a shattered combat veteran, for example, while smoke from burning leaves might trigger smell-based memories of pyres for a genocide survivor. Among the anxiety disorders linked to conditioned fear responses is one that's much in the news: post-traumatic stress disorder.
For more than a decade, Vadim Bolshakov, an HMS associate professor of psychiatry and director of McLean Hospital's Cellular Neurobiology Laboratory, has explored fear-driven disorders by investigating their molecular bases in the brains of rats. One early finding from his laboratory showed that learned fear changes the way the animals' brains operate, offering a mechanism for conditioned fear's persistence.
Bolshakov and colleagues taught rats to associate a harmless stimulus, a tone, with a painful event, a shock to their feet. The researchers found that neurons in the rodent amygdala exhibited remarkable sensitivity to the tone, so much so that the neurons continued to fire after the stimulus was removed. This sensitivity, known as long-term potentiation, is important to memory acquisition. It is normally modulated by glutamate, a chemical that is released into the synaptic spaces between neurons when a message is being passed, but then is deactivated to prevent message over-expression. Bolshakov's team showed that the amygdala's heightened sensitivity was the result of too much glutamate, either because the clean-up process failed or, as the researchers postulated, because production of the chemical went into overdrive.
Other studies by Bolshakov and colleagues identified two proteins essential to the innate and learned fear responses. When the researchers blocked production of one of the proteins, stathmin, fear-conditioned mice were less able to recall the learned fear-and lost the ability to recognize dangers that normally would have kicked their innate fear response into high gear. Blocking the gene that produced a protein known as transient receptor potential channel 5, normally found in high concentrations in the amygdala, decreased the rodents' neurons' sensitivity to cholecystokinin, a neuropeptide released when the innate fear response is triggered or a learned fear is recalled.
These insights are welcomed by Roger Pitman, an HMS professor of psychiatry, and Mohammed Milad, an HMS assistant professor of psychiatry. Based at Massachusetts General Hospital, these researchers seek to tease out treatments for people with anxiety disorders such as post-traumatic stress disorder.
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