Experiments on mice conducted by Howard Hughes Medical Institute researchers have provided significant new insights into what changes occur in the brain when the animal is conditioned to feel safe in stressful situations.
Columbia University researcher Eric R. Kandel and his colleague Daniela D. Pollak said that the experiments showed that the mice developed a conditioned inhibition of fear, which they called "learned safety.
The researchers said that the behavioural changes observed in the mice squelched anxiety as effectively as antidepressant drugs like Prozac.
The new findings attain significance because they reveal in elegant detail how behavioural conditioning can affect the brain, say the researchers.
Knowing how behavioral intervention works at the molecular and cellular levels, according to them, might prove to be an interesting route to identifying novel drugs to treat depression and anxiety disorders.
"I've always been interested in how psychoanalysis works. Since it is a learning experience, there must be a biological basis in the brain," said Kandel, who trained as a psychiatrist.
He pointed out that pathological forms of learned fear can lead to debilitating anxiety disorders, post-traumatic stress syndrome, or depression in some people.
However, learned safety reduces chronic stress, one of the hallmarks of depression and other psychopathologies, he added.
"The ability to identify, develop, and exploit conditions of safety and security is central to survival and mental health," said Kandel, "but little is known of the neurobiology of these processes."
During the study, the researchers trains some mice to associate safety or fear with specific auditory tones.
While the auditory stimulus was paired with a mild shock to the mouse's foot for fear conditioning, it was not followed by a shock for safety conditioning.
The experiments showed that the safety-conditioned mice learned to associate the tone with the absence of danger, and displayed less anxiety in the presence of the safety signal.
Kandel's team then placed the safety-conditioned mice into a pool of water for a swim test, commonly used by researchers to measure how antidepressant drugs affect the behaviour of mice.
"In this seemingly desperate situation ? where the mice have no option to escape from the water - they start to show signs of behavioural despair that are ameliorated by antidepressant medications. We found that the mice trained for safety could overcome their sense of hopelessness in the swim test," the researcher said.
He said that the antidepressant effect in the safety-conditioned mice was similar and comparable in magnitude to treatment with the drug fluoxetine (Prozac).
The researchers then studied how learned safety influenced the development of newborn cells in the dentate gyrus, a structure located in a region of the brain called the hippocampus that spawns new neurons even in adult animals.
They found that the mice that had been conditioned for safety had a greater number of newborn cells in the dentate gyrus.
When the group used radiation to blunt the birth of new cells in the dentate gyrus, it was found that their interventions both slowed safety learning and stunted the antidepressant effects of learned safety.
The researchers also found that safety learning ramped up expression of brain-derived eurotrophic factor (BDNF) in the dentate gyrus. BDNF is a growth factor that promotes the growth and differentiation of new neurons and their connections.
Genetic analyses revealed that in the amygdala, the brain's fear centre, learned safety tunes the expression of key components of the dopamine neurotransmitter system and the neuropeptide system, both of which are thought to influence learning, mood, and cognition.
Kandel said that his group was intrigued to find that learned safety did not influence serotonin, the neurotransmitter typically targeted by antidepressant drugs.
Learned safety appeared to influence levels of both dopamine and neuropeptide neurotransmitters, suggesting new avenues for antidepressant drug development, he said.
"This has given us several interesting insights and led us to a number of potential targets for new drugs," he added, noting that there were already agents in development that influence the dopamine and neuropeptide pathways.