When we are exposed to stimuli that we perceive as threatening, a certain neural mechanism is fired that lets us learn fear. The amygdala has long been considered key to this process, but which part of this brain region is at the core of fear learning?

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The amygdala is also known as the brain's 'fear hub,' but which part of this brain region is actually at the center of fear learning?

Fear learning is the process by which we register certain stimuli or situations as potentially dangerous, allowing us to adapt to the contexts that we find ourselves in and preserve our own safety if the brain perceives a threat.

The downside of this mechanism is that it sometimes backfires, resulting in fight, flight, or freeze reactions to threats that do not exist in the present moment. One disorder characterized by this unintended effect is post-traumatic stress disorder (PTSD), in which memories of a traumatic event resurface unbidden and trigger a counterproductive fight, flight, or freeze response.

New research from the Cold Spring Harbor Laboratory in Laurel Hollow, NY, takes a closer look at the brain mechanism responsible for fear learning and reconsiders the role of the amygdala in this process.

Lead researcher Prof. Bo Li and his team conducted a series of experiments on mice and noted that, although the lateral amygdala has always been held as the key region in which fear associations are formed, it may actually be the central amygdala that is responsible.

The researchers' findings were published earlier this week in the journal Nature Neuroscience.

Central amygdala controls fear learning

The amygdala is a part of the brain typically described as being the shape of "twin" almonds. This brain region is implicated in emotional behavior and has been widely studied in relation to fear.

Scientists often use aversive learning — that is, a conditioning to avoid unpleasant stimuli, such as a mild electric shock — to study the brain circuitry responsible for acquiring memories of fear and dislike.

So far, research has suggested that the lateral amygdala — which is the region of the amygdala that "flanks" the central nucleus — is responsible for establishing connections between certain stimuli and the perception of potential danger.

In the new study, Prof. Li and his colleagues conducted experiments in mice that they exposed to unpleasant stimuli in order to test which part of their amygdalae the fear associations were formed in.

The first experiment involved inflicting mild electrical shocks to the mice's feet, following which the researchers imaged both the central and lateral amygdala of the animals' brains.

Contrary to what is currently believed, the scans indicated that the link between the stimuli and threat perception was established in the central nucleus of the amygdala, rather than in the lateral amygdala, although the latter still played a role in aversive learning.

In this experiment, the lateral amygdala played a secondary role, functioning as an output channel for the information established in the central amygdala.

The researchers also blocked PKC-delta neuronal cells, which are a type of neuron found in the central amygdala so named after the protein kinase C-delta enzyme that they express.

It was noted that mice whose PKC-delta neuronal cells had been blocked showed dampened activity in the lateral amygdala, suggesting that fear learning did not originate there, but in the central nucleus instead.

Neural cells in central amygdala may be key

In additional experiments, Prof. Li and team used optogenetics — a technique that uses pulses of light to control neural activity — to induce certain aversive memories in mice.

Here, they used colored laser light pulses to activate PKC-delta neurons in the central amygdala. "This causes no pain to the mice, but they don't like it — it makes them feel uncomfortable, just as getting a mild shock makes them uncomfortable. It's the kind of stimulation that leads to an aversive memory, the kind you learn from," explains Prof. Li.

The mice exposed to the optogenetic stimulus associated the discomfort of this experience with the cage chamber in which they had undergone this experiment. As a consequence, the animals later avoided going back to this chamber; they linked it with a sense of discomfort.

As Prof. Li explains, the exposure to pulses of light was not actually painful, but it created the illusion of pain at a neural level.

This suggests that the activation of PKC-delta neuronal cells could play a central role in aversive learning.

If these findings are confirmed by further research, Prof. Li and his colleagues hope that they may provide new pathways to treating anxiety disorders such as PTSD.