Research finding suggests possibilities for future treatment of anxiety disorders

Researchers at the University of Puerto Rico, School of Medicine have found a way to pharmacologically induce a memory of safety in the brain of rats. As reported in the June, 4 2010 issue of Science, administering brain-derived neurotrophic factor (BDNF) into the prefrontal cortex prevented rats from expressing fear to a tone that had been previously paired with a shock. Rats given BDNF acted as if they had received repeated presentations of the tone without the shock, a procedure called extinction. "The surprising finding here is that the drug substituted for extinction training, suggesting that it induced a memory for extinction", said Dr. Gregory Quirk of the Department of Psychiatry, who led the investigation. This finding could suggest new treatments for individuals suffering from anxiety disorders.

A common laboratory procedure used to study fear is called fear conditioning, which involves pairing a tone with a mild footshock. After several such pairings, rats learn to freeze to the tone, in expectation of the shock. Conditioned fear responses can be extinguished by repeatedly presenting the tone without the shock. Prior work has shown that extinction training does not erase the fear memory, but creates a new memory trace responsible for a sense of safety. Memories are formed by altering the connections between neurons, a process known as synaptic plasticity. One structure critical for extinction memory is the infralimbic prefrontal cortex (ILC). Drugs that block synaptic plasticity impair the formation of extinction memory when injected into the ILC, causing rats to continue freezing at high levels after extinction training. This raises the question, could drugs that facilitate synaptic plasticity in ILC strengthen extinction?

One candidate drug is brain-derived neurotrophic factor (BDNF), a naturally occurring growth factor involved in multiple forms of learning. BDNF permits a learning experience to increase the size and strength of synaptic contacts between neurons. Previous work from other groups had shown that BDNF in the amygdala and hippocampus was involved in extinction learning, but its involvement in ILC was unknown. Rats were conditioned to fear a tone by pairing it with a footshock, until they showed a freezing response to the tone. The following day, instead of extinction training, rats were infused with BDNF into the ILC. The next day, BDNF-infused rats showed little freezing to the tone, as if they had received extinction training. Additional experiments showed that the "BDNF-extinction" resembled actual extinction in that it did not erase the original fear memory and required NMDA glutamate receptors. Control experiments showed that the BNDF did not alter other behavioral variables such as conditioning, locomotion, or general anxiety, suggesting that the memory was specific for extinction.

Could naturally occurring variations in brain BDNF levels explain why some individuals extinguish better than others? To address this, the researchers measured BDNF protein in rats that showed successful vs. failed extinction. Failed extinction was associated with deficient BDNF in the hippocampus, a structure that projects to ILC and is important for extinction. They further showed that augmenting BDNF in the hippocampal-ILC pathway was sufficient to induce extinction. This suggests that BDNF infused into ILC mimics the BDNF normally released from the hippocampus during extinction, serving to strengthen synaptic connection within ILC during extinction.

Failure to extinguish fear is thought to contribute to anxiety disorders, such as post-traumatic stress disorder (PTSD). People with PTSD have a smaller than normal hippocampus and ILC. "Our finding suggests that augmenting BDNF in these circuits may ameliorate PTSD and perhaps other disorders such as addictions" said Dr. Jamie Peters, the post-doctoral researcher who collaborated with Quirk on this project. The focus now is to look for ways to augment BDNF's actions in the brain, which might include anti-depressant medications and even exercise. Dr. Thomas Insel, Director of the National Institute of Mental Health, which funds Quirk and Peter's research said, "This work supports the idea that medications could be developed to augment the effects of BDNF, providing opportunities for pharmaceutical treatment of post-traumatic stress disorder and other anxiety disorders."