Fear is an important reaction that warns us and protects us from danger. But when anxiety reactions are out of control, this can lead to persistent fears and anxiety disorders. In Europe, about 15 percent of the population is affected by anxiety disorders. Existing therapies remain largely non-specific or are generally ineffective because of the lack of a detailed neurobiological understanding of these disorders.
What has been known so far is that different nerve cells interact with each other to regulate fear responses by promoting or suppressing them. Different circuits of nerve cells are involved in this process. A kind of “tug of war” takes place, with one brain “winning” and overwriting the other, depending on the context. If this system is disrupted, for example when anxiety reactions are no longer suppressed, this can lead to anxiety disorders.
Recent studies have shown that certain groups of neurons in the amygdala are crucial for the regulation of anxiety reactions. The amygdala is a small almond-shaped brain structure in the center of the brain that receives information about anxious stimuli and passes them on to other brain regions to generate fear responses. This causes the body to release stress hormones, altering heart rate in response to fighting, flight or freezing.
Now a group led by professors Stephane Ciocchi of the University of Bern and Andreas Luthi of the Friedrich Miescher Institute in Basel has discovered that the amygdala plays a much more active role in these processes than previously thought: Not only is the central amygdala a “hub” to generate fear responses, but it contains neuronal micro-circuits that regulate the suppression of anxiety responses. In animal models, inhibition of this microcircuit has been shown to lead to long-term fear behavior. However, once activated, behaviors return to normal despite previous anxiety reactions. This shows that neurons in the central amygdala are highly adaptable and essential for suppressing anxiety. These results were published in the journal Nature communication,
“Disturbed” suppression leads to long-lasting fear
The researchers, led by Stephane Ciocchi and Andreas Luthi, examined the activity of central amygdala neurons in mice during the suppression of anxiety reactions. They were able to identify different cell types that influence the behavior of the animals. For their study, the researchers used several methods, including a technique called optogenetics, which allowed them to precisely block the activity of an identified neuronal population in the central amygdala producing a specific enzyme – using pulses of light. This damaged the suppression of fear responses, after which animals became overly frightened. “We were surprised at how strongly our targeted intervention in specific central amygdala cell types affected anxiety responses,” said Ciocchi, assistant professor at the Institute of Physiology, University of Bern. “The optogenetic silence of these specific neurons completely abolished the suppression of fear and provoked a state of pathological fear.”
Important for developing more effective therapies
In humans, dysfunction of this system, including deficient plasticity in the nerve cells of the amygdala described here, may contribute to the limited suppression of anxiety disorders reported in patients with anxiety and trauma-related disorders. A better understanding of these processes will help to develop more specific therapies for these disorders. “However, further research is needed to investigate whether discoveries made in simple animal models can be extrapolated to human anxiety disorders,” Ciocchi adds.
This study was conducted in collaboration with the University of Bern, the Friedrich Miescher Institute and international collaborators. It was funded by the University of Bern, the Swiss National Science Foundation and the European Research Council (ERC).
Systems Neuroscience Group, Institute of Physiology, University of Children
Neuronal diversity is a characteristic of cortical networks. In the hippocampus, different neuronal cell types interact together through selective synaptic contacts and neuronal activity patterns. We investigate how different forms of emotional and cognitive behavior arise within complex neural circuits of the ventral CA1 hippocampus, a brain region instrumental to context-specific emotional memories, anxiety, and purposeful actions. We hypothesize that different behavioral programs are implemented through the selective recruitment of micro- and large-scale neuronal circles of the ventral CA1 hippocampus. To identify these circadian motifs, we combine single unit recordings of ventral CA1 GABAergic internal neurons and projection neurons, selective optogenetic strategies, cell-type specific viral detection, and rodent behavioral paradigms. The results of our experimental approach will determine fundamental neuronal calculations underlying learning and memory within higher cortical brain regions.
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