Stress Hormones Sensitize Fear Circuits in the Brain

What's the science?

Fear and stress can induce the ‘fight-or-flight’ active response or a passive ‘freezing’ response. Associative memories can form when a cue is associated with an aversive (i.e. negative) experience, and these cues often trigger a freezing (i.e. fear) response later on. Dysfunction of the brain circuitry involved in this response can lead to disorders such as post-traumatic-stress disorder and generalized anxiety disorder. We know that thalamus-amygdala circuitry and hormones released within the amygdala are involved in these disorders, however, we still don’t understand how it underlies ‘freezing’ behavior. This week in Molecular Psychiatry, Pliota and colleagues test whether thalamus-amygdala circuitry and hormones within the amygdala contribute to freezing behavior after stress.

How did they do it?

Part1 -- Mice underwent two elevated maze exploration task trials (a task typically used to assess anxiety behavior in mice including ‘fight or flight’ vs. freezing responses) separated by ten unpredictable foot shocks to induce fear memory. Passive freezing responses generally act as a coping mechanism when dealing with unpredictable stressful stimuli. The authors used an early gene approach (an approach that measures early gene responses to stimuli) to assess which brain regions were involved in the anxiety response after foot shock. They then performed calcium imaging (to measure neuronal activity) during unpredictable foot shock, and during a maze exploration task that followed. This imaging technique determined which brain regions were activated by these two paradigms.

Part 2 -- They then performed a series of experiments including optogenetics, electrophysiology & chemogenetics to test how the stress circuitry found underlies anxiety behavior (active vs. passive).

What did they find?

Part1 -- Mice exposed to the unpredictable foot shock later demonstrated less exploration in the maze task, indicating greater passive ‘freezing’ responses compared to control mice. They found that the periaqueductal grey area and the periventricular thalamus (previously implicated in anxiety) were brain regions recruited after foot shock. Using Calcium imaging, they found that the thalamus was 1) activated in response to foot shock, and 2) more active during the maze exploration following the unpredictable foot shock (as opposed to no previous foot shock).

Part 2 -- They used a retrograde tracer to show that thalamus projections to the amygdala were more active during the maze exploration after foot shock. They then used optogenetics to activate the thalamus-amygdala circuit and found that in later maze exploration, behavior mimicked that after foot shock, whereas deactivation of this circuit counteracted the passive behaviors seen in the maze exploration after foot shock. These results suggest that the thalamus-amygdala circuit specifically is reinforced during stress and leads to future ‘freezing behavior’. They used electrophysiology to show that activation of neurons in thalamus selectively activates neurons in the amygdala that express corticotropin releasing hormone (a stress hormone). Using designer drugs (genetically engineered receptors) to activate neurons that release corticotropin releasing hormone increased passive behaviors in the maze task. Lastly, they used microdialysis to show that corticotropin releasing hormone is actually released in the amygdala after foot shock. They blocked this hormone by injecting an antagonist to block the receptors on neurons, and found that the passive behaviors were reduced, suggesting that this hormone (typically released from the amygdala) mediates the passive freezing response to foot shock.

What's the impact?

This is the first study to show a specific thalamus-amygdala pathway and the release of corticotropin releasing hormone mediates passive anxiety behaviors. We now have a better understanding of the brain circuitry involved in the 'freezing' response to stressful events. These findings have important implications for understanding the dysfunctional circuitry in disorders like post-traumatic stress disorder and generalized anxiety disorder.

Pilota et al., Stress peptides sensitize fear circuitry to promote passive coping. Molecular Psychiatry (2018). Access the original scientific publication here.