UCLA neuroscientists discovery distinct molecular key to overcoming fear

In a discovery with implications for treatment of anxiety disorders, UCLA Neuropsychiatric Institute investigators have identified a distinct molecular process in the brain involved in overcoming fear. The findings will be published in the Oct. 15 edition of the Journal of Neuroscience.

The study of how mice acquire, express and extinguish conditional fear shows for the first time that L-type voltage-gated calcium channels (LVGCCs) — one of hundreds of varieties of electrical switches found in brain cells — are required to overcome fear but play no role in becoming fearful or expressing fear. The findings suggest that it may be possible to identify the cells, synapses and molecular pathways specific to extinguishing fear, and to the treatment of human anxiety disorders.

“Brain plasticity, or the ability of the central nervous system to modify cellular connections, has long been recognized as a key component to learning and memory,” said Dr. Mark Barad, the UCLA Neuropsychiatric Institute’s Tennenbaum Family Center faculty scholar and an assistant professor in-residence of psychiatry at the David Geffen School of Medicine at UCLA. “The discovery of a distinct molecular process in overcoming fear bodes well for development of new drugs that can make psychotherapy, or talk therapy, easier and more effective in treating anxiety disorders. More broadly, the findings also suggest that distinct molecular processes may be involved in the expression and treatment of other psychiatric disorders.”

Both the acquisition and extinction of conditional fear are forms of active learning. The acquisition of conditional fear requires a unique pairing of an initially neutral conditional stimulus with an aversive unconditional stimulus. In this research, the conditional stimulus was a tone and the unconditional stimulus was a mild foot shock.

Although extinction, the reduction of conditional responding after repeated exposures to the conditional stimulus alone, might initially appear to be a passive decay, or erasure of this association, many studies indicate that extinction is new inhibitory learning, which leaves the original memory intact.

In examining this process, UCLA researchers used injections of two LVGCC inhibitors — nifedipine and nimodipine — to test whether LVGCC activity is required for the 1) acquisition, 2) expression and 3) extinction of conditional fear. Results showed that blocking LVGCC activity had no effect on the acquisition or expression of fear, but effectively prevented extinction.

The research was supported by a National Alliance for Research on Schizophrenia and Depression Young Investigator Award, and by the Forest Award of the West Coast College of Biological Psychiatry.

Other investigators involved in the project were Chris Cain of the UCLA Interdepartmental Program in Neuroscience and Ashley Blouin of the UCLA Department of Psychiatry and Biobehavioral Sciences. Barad also is affiliated with the UCLA Brain Research Institute.

The Tennenbaum Family Center at the UCLA Neuropsychiatric Institute was created earlier this year with a four-year, $1 million gift from Michael E. and Suzanne Tennenbaum. Michael Tennenbaum is managing member of Tennenbaum and Company, a private Los Angeles-based investment firm he founded in 1996.

In addition to the faculty scholar program, the center is encouraging research into brain plasticity by providing seed money to promising research projects and offering graduate student and post-doctoral fellowship support.

The UCLA Neuropsychiatric Institute is an interdisciplinary research and education institute devoted to the understanding of complex human behavior, including the genetic, biological, behavioral and sociocultural underpinnings of normal behavior, and the causes and consequences of neuropsychiatric disorders.