Researchers report progress in untangling a web of complexities that they believe can give rise to social anxiety disorder.

They have amassed evidence directly linking susceptibility to social anxiety disorder with problems in a neural circuit that runs between a part of the cerebral cortex called the orbitofrontal cortex (OFC) and the BLA, a part of the amygdala, an area deep in the brain involved in processing emotions.

The team, led by two BBRF Scientific Council members, identifies the source of the problem in the OFC-BLA circuit: insufficient amounts of an important growth factor called BDNF in the affected regions, specifically during adolescence.

Francis S. Lee, M.D., Ph.D., of Weill Cornell School of Medicine, and B.J. Casey, Ph.D., of Yale University, along with colleagues including Conor Liston, M.D., Ph.D., and M.D.-Ph.D. candidate Anfei Li, performed imaging experiments in humans as well as a variety of experiments in mouse models of anxiety. Some of the mice were bred to carry the human version of a genetic variant (called Val66Met) in the BDNF gene that impairs the ability to secrete the BDNF protein.

In both people and mice carrying the BDNF genetic variation, the researchers noted that OFC-BLA circuit is disrupted, due to “insufficient BDNF bioavailability,” specifically during adolescence.

Experimentally limiting BDNF availability in mice beginning in adulthood had no impact on susceptibility to social anxiety behaviors. The damage was done only when immature animals lacked the ability to secrete sufficient amounts of BDNF to support properly working OFC-BLA circuitry. Boosting expression of BDNF in adolescent mice carrying the adverse variation appeared to enable these mice to be free of social anxiety once they matured.

It is not fully understood why plentiful BDNF during a critical window in time translates years later into much lower risk of social anxiety, although it may reflect the critical role of BDNF in the proper development of this specific circuit that regulates social behaviors, the team says.

The circuit in which the fault occurs, the team acknowledges, “is likely a part of a larger and complex social network” consisting of other circuits too, not yet clearly delineated. The team is confident that malfunction of OFC-BLA circuit “is social-specific,” and rather than affecting sociability, generally, seems to affect social behavior specifically when an individual confronts “challenging social situations.”

Noting their ability to “rescue” young mice born with the genetic variant that affects BDNF secretion—by boosting BDNF levels—the researchers speculate that therapies and medicines able to elevate levels of BDNF, including exercise, environmental enrichment, and antidepressants, may one day be tested as correctives for people with behavioral alterations caused by the BDNF genetic variation.

In addition to being members of the BBRF Scientific Council, Dr. Lee is a 2010 BBRF Independent Investigator and 2005 and 2002 Young Investigator; and Dr. Casey is the 2015 Ruane Prizewinner for Outstanding Achievement in Child and Adolescent Psychiatric Research. Dr. Liston is a 2013 BBRF Young Investigator.