When Fear Gets Out of Hand: Fear Generalization & PTSD

The fight or flight response is a physiological alert system that protects the body from perceived threats. Patients with post traumatic stress disorder (PTSD) fail to discriminate dangerous stimuli from safe stimuli. For these patients, an excessive generalization of fear results in fearful responses, even from cues that are neutral or signal safety. One of the brain regions implicated in this behavior is the amygdala, an almond shaped structure located deep in the brain. Part of the limbic system, the amygdala, works with the hippocampus and cortex to modulate emotional reactions, memory, and decision making. Over-activation of the amygdala is thought to be a main mechanism for the fear generalization response in PTSD. However, research of this in humans has been impeded by our ability to visualize fear in the awake human brain: the resolution of MRI cannot detect changes in activity in individual neurons.

In a recent study published in Nature Neuroscience, S. Ghosh and S. Chattarji studied the neural circuitry of fear generalization in a rat model. Rats were trained on a fear conditioning task where a tone is paired with a shock. When that tone is played again, even in the absence of the shock, the rats freeze in fear—a conditioned tone. However, when a new tone is played, the rats do not freeze to this unconditioned tone, indicating they only associate the original tone with the shock. The investigators recorded the electrical signals that neurons use to communicate with each other by placing electrodes that amplify this activity in the amygdalae of the rats during fear conditioning. What they found was quite interesting— individual neurons responded differently during fear conditioning. Some neurons responded only to the fear-conditioned (cue-specific) tone. Others responded to both the unconditioned and conditioned (generalized) tones. When rats were trained to generalize their fear (this was done by increasing the intensity of the shock paired with the unconditioned tone), the rats froze upon hearing both the conditioned and unconditioned tones. When the researchers examined neurons in the amygdalae, they saw an increase in the number of generalizing neurons compared to the cue-specific neurons.

Ghosh and Chattarji also assessed neuronal excitability in the amygdala, and found that neuronal excitation was higher overall after fear generalization. They tested whether activation of cAMP-PKA signaling, known to be important in neuronal excitability, was important for fear generalization. Rats were trained on the baseline fear-conditioning task and their amygdalae were infused with a drug that increases cAMP signaling. Surprisingly, elevation of cAMP signaling in the amygdala was sufficient to induce both the behavioral and physiological manifestation of fear generalization even in the absence of fear generalizing shocks. These results indicate that that cAMP-PKA mediated excitation in the amygdala may be over-activated in patients with PTSD, and suggest that modulation of this pathway may be a useful therapeutic target to help PTSD patients manage their fear.

Publication

1. Ghosh S and Chattarji S (2015) Neuronal encoding of the switch from specific to generalized fear. Nature Neuroscience 18:112–120. doi: 10.1038/nn.3888