Researchers have discovered a brain circuit that appears to enable both rodents and people to inhibit their threat response in the presence of a learned “safety signal.” The research suggests it may be possible to develop a new way of treating people who have difficulty controlling their fearful or anxious responses to perceived threats.

Difficulty controlling fear when it is not an appropriate response to current conditions is a symptom often seen in people with anxiety disorders as well as those with post-traumatic stress disorder (PTSD). The best available treatment for such people is cognitive behavioral therapy (CBT), specifically aimed at exposing an individual to a stimulus that triggers their fear response and teaching them to extinguish that fear (“fear extinction”) when an actual threat is not present.

A team led by Dylan Gee, Ph.D., of Yale University, a 2015 BBRF Young Investigator, and Francis S. Lee, M.D., Ph.D., a BBRF Scientific Council member and three-time grantee, of Weill Cornell Medicine, explain in a paper appearing in the Proceedings of the National Academy of Sciences that exposure-based therapy calls for patients to repeatedly and systematically confront fear-provoking stimuli with the goal of reducing anxiety. But they note that up to 50% of individuals with anxiety disorders do not respond sufficiently to such therapy, while up to 27% of patients drop out of treatment. In some instances, people halt therapy “because of the aversive nature of the [fear] exposures themselves.”

The team, which also included 2013 BBRF Young Investigator Conor Liston, M.D., Ph.D., as well as Heidi Meyer, Ph.D., of Weill Cornell Medicine, and Paola Odriozola, Ph.D., of Yale University, set out to discover whether it might be possible to inhibit fear not through exposure to fearful stimuli but via the introduction of “safety signals.” In the context of behavioral testing, these are cues that the individual learns to associate with a lack of threat. If the safety cue was presented in the presence of the threat cue, the researchers hypothesized, perhaps the individual could be conditioned to inhibit their fear response, a response they call “conditioned inhibition.”

Experiments were performed in rodents and with human subjects, in which the team sought to identify neural pathways that are activated when an individual learns a safety signal. In the rodents, they revealed a circuit leading from the ventral portion of the hippocampus—a part of the brain in mammals that processes the context associated with anxiety—to the prelimbic cortex. In humans, the corresponding pathway was similarly engaged, leading from the ventral hippocampus to the dACC, or dorsal portion of the anterior cingulate cortex.

When threat cues are presented, the team wrote, “these regions are ‘out of sync’ when a threat is imminent.” When there is no threat, however, or in the presence of a signal that the situation is indeed “safe,” such an imbalance would correspond with a difficulty extinguishing fear or anxiety.

The pathway the researchers discovered leading from the ventral hippocampus that can inhibit the response to threat (in the presence of learned safety cues) “diverges from the circuitry involved in extinction learning” that is central in CBT which addresses fear- and stress-related anxiety.

Their hope is that targeting this distinct pathway using safety signals “may provide an effective alternative or means to enhance treatment for individuals for whom the efficacy of exposure-based CBT is otherwise limited.”

The next steps in this research, the team suggested, will involve attempting to enhance anxiety reduction in individuals with anxiety disorders, and during childhood and adolescence, when anxiety disorders peak.