Mice that were conditioned to feel safe in stressful situations showed the same ability to overcome fear and depression as mice that were treated with an antidepressant, according to a new study by Eric Kandel and colleagues at Columbia University and published in the Oct. 9 Neuron.

While the evolution of instinctive and learned fear has been essential for survival of organisms from invertebrates to mammals, learned fear in humans has also been associated with psychopathologies such as anxiety, depression and post-traumatic stress disorder. Previous studies have explored “conditioned inhibition” as a way to mitigate expressions of learned fear. In the current study, Kandel and colleagues looked at the behavioral consequences of this kind of conditioning, and its associated molecular pathway.

Mice were first conditioned to respond to a safety signal, in a process referred to as “learned safety,” and then subjected to a forced swim test. In this test, depressed animals stop swimming much earlier than their normal counterparts. Mice that had been conditioned to the safety signal began swimming again when the signal was given, as did mice that were given an antidepressant. The safety-trained mice also recovered their preference for sweet foods when they heard the safety signal after being exposed to unpredictable chronic mild stress.

When the researchers examined what was happening at the molecular level in these mice, they found that, like an antidepressant, learned safety stimulated neurogenesis, or cell growth, in the hippocampus and increased the expression of a

neuropeptide called brain-derived neurotrophic factor. Unlike many antidepressants, learned safety appeared to affect dopamine and neuropeptide neurotransmitters rather than on the serotonin pathway.

“That the molecular pathway is different suggests that you could develop new drugs, a new class of medication to treat depression,” Kandel says. Follow-up experiments would further study the role of the dopaminergic system in learned safety, he adds.