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doi:10.1038/nindia.2014.166 Published online 9 December 2014

What turns fear into paranoia?

Priyanka Pulla

A panic stricken survivor of the Bangladesh Liberation War, 1971.
© Penny Tweedie / Alamy
War veterans with post traumatic stress disorder get startled when a door is banged because it sounds like firing in a battlefield. Rats and rabbits subjected to electric shocks freeze each time they hear similar zapping sounds.

What turns the rational fear of a truly dangerous event into panic for everyday sights and sounds? Scientists from Bangalore’s National Centre for Biological Sciences (NCBS), have found that the switch from a specific fear to generalised fear happens at the level of individual neurons in an almond shaped part of the brain called the amygdala1. The moment a rat stops discriminating between a sound that augurs a painful shock and similar but safer sounds, several neurons in its brain lose the ability to do the same. What’s more, activating a signaling pathway called cAMP-PKA makes rats more prone to generalizing their fear. 

Neurobiologists Sumantra Chattarji and Supriya Ghosh suggest that blocking this pathway could open the door to new therapies for post traumatic stress disorder (PTSD). The duo took a cue from previous brain imaging studies on PTSD patients, which showed they had hyperactive amygdalae when the patients reacted to fearful stimuli2.

Since magnetic resonance imaging (MRI) doesn't reveal much, the neurobiologists went a step ahead and designed a Pavlovian experiment for rats. They taught rats to distinguish between a safe tone and a dangerous one. Both tones were of different frequencies, but the dangerous one was followed by an electric shock each time, while the safe one signaled nothing. The rats quickly learnt to distinguish between them, and would freeze each time the dangerous tone was played, but do nothing for the other.

Now, the researchers placed electrodes in the amygdalae of the rats to see how each neuron reacted when the rats heard the sounds. Most neurons seemed to know the difference between the harmless tone and the dangerous one: they fired in response to the latter, but not the former. “But there was a small aberrant population of neurons — about five percent — that didn’t get it,” explains Chattarji. These neurons fired for both tones. The researchers called them generalised neurons.

Next, the NCBS team increased the intensity of the electric shock. As expected the rats began to fear both tones equally, and froze the same amount each time they heard either. When the scientists peered into the rats’ amygdalae this time, they found that the neurons had switched sides too. The same neurons which could discriminate between the safe and dangerous tones earlier, were now firing for both. In fact, some of the neurons were firing more for the safe tone than they were for the other. “They went completely bonkers. Like politicians in the parliament, they had changed colour and started firing for both sounds,” Chattarji says.

In another experiment, the researchers found that it was possible to get rats to generalise their fear more quickly by activating the cAMP-PKA pathway using a chemical called forskolin. It is likely that the same pathway is at work in inducing generalised anxiety in PTSD patients. Now that we know this, says Chattarji, it may be possible to treat anxiety in PTSD patients by targeting this pathway.

The finding could also help identify people at greater risk of PTSD, says Eero Castren, a neuroscientist from the University of Helsinki. “Since it is hardly feasible to treat everybody ever exposed to a traumatic event chronically with a drug, is it possible to identify individuals that are most likely to suffer a transition from specific to generalized fear? This study provides valuable new information to this," Castren says. 

Chattarji adds that it may be a good idea to vet new PTSD drug-leads for action along the cAMP-PKA pathway. Going by their findings, such molecules would be more effective against the generalised anxiety that all PTSD patients experience.


References

1. Ghosh, S. & Chattarji, S. Neuronal encoding of the switch from specific to generalized fear. Nat. Neurosci. (2014) doi: 10.1038/nn.3888

2. Bryant, R.A. et al. Enhanced amygdala and medial prefrontal activation during nonconscious processing of fear in posttraumatic stress disorder: An fMRI study. Hum. Brain Mapp. 29, 517–523 (2008) doi: 10.1002/hbm.20415