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Findings in animals often lead scientists to reconsider not just basic human functions like sleep but also traits once considered quintessentially human, such as how we learn and store what we have learned. Columbia's Kandel asserts that animal-based molecular biology soon will affect psychiatry as profoundly as it has neurology.
Nearly 50 years ago, against the advice of his mentors, Kandel elected to study fear and learned memory of fear in a highly unlikely subject: a giant marine snail called Aplysia californica, which grows up to a foot long and can weigh several pounds. (Kandel nonetheless refers to Aplysia as “beautiful.”)
Many scientists of the day thought the neurobiology of an invertebrate could have little relevance to the mental functions of humans. Chief among the doubters, Kandel recalls, were students of behavior: psychiatrists, psychoanalysts, and psychologists. At that time only two scientists in the world bothered to study this snail at all.
Humans spend about a third of their lives asleep, but nobody really knows why. Sehgal's finding provides evidence for the theory that sleep is necessary for consolidating memory.
But in a body of work spanning decades, Kandel and other researchers used Aplysia, and later mice, to establish a molecular basis for memory storage and learning in the brain. Scientists working with rats eventually traced the memory of fear to the amygdala and the body's expression of fear to the hypothalamus. Using these findings to explore the molecular underpinnings for fear in mice, Kandel discovered that they bear great resemblance to the mechanisms observed in Aplysia.
Now it appears that happiness may be similarly discernible in the brain. In a recently published study, Kandel and Columbia colleague Michael Rogan showed that mice conditioned to associate a sound with safety showed reduced electrophysiological activity in the amygdala, perhaps representing a decrease in fear. At the same time, they showed increased activity in parts of the dorsal striatum involved in positive emotion and reward. “These mice just walk around unafraid, as if they own the place,” says Kandel.
Nearly 30 percent of Americans suffer an anxiety disorder at some point in their lives, and the finding has made Kandel wonder if certain of these disorders might result from defects in the neural systems that communicate security.
Fortunately, the gap between human anxiety and animal fear may prove smaller than once thought. Scientists have yet to discover an Aplysia with full-blown panic disorder, of course, but rodent models of depression have led directly to a number of useful medications. Better models, though, may soon bring better therapies.
Scientists studying depression, along with drugs to reduce it, have relied largely on wild-type mice that were “socially defeated.” Submissive mice were housed in containers with dominant mice, and the behavior developing in the submissives was judged to be as close to depression as researchers could get.
But last year HHMI investigator Li-Huei Tsai, a neurobiologist now at the Massachusetts Institute of Technology, led a team that developed mutant mice whose disease may more closely mimic that of humans.