Neural pathways in amygdala regulates fear response

Fear arises in the almond-shaped brain structure known as the amygdala. It is the amygdala which processes the strange noise, shadowy figure or scary face and not only triggers palpitations or nausea but can also cause us to flee or freeze. That much has long been known about the function of this part of the brain. What remains largely unclear, however, is precisely how fear develops, and which of the countless neurons in the amygdaloid region are involved in this process. But finding answers to these questions is vital for those who wish to improve the quality of life for people suffering as a result of traumatic experiences. In particular, patients with post-traumatic stress or anxiety disorders could benefit from the elucidation of neural processes in the amygdala.

Neurobiologists at the Friedrich Miescher Institute for Biomedical Research (FMI, part of the Novartis Research Foundation) have become the first to identify neural pathways and types of neurons in the amygdala which play a key role in the behavioral expression of fear. In two studies published in the latest issue of Nature, they show that there are clearly defined types of neurons in the amygdala which fulfill specific functions in the processing of fear inputs and subsequent fear responses. These cell types are organized in circuits, connecting neurons and various areas within the amygdala.

In collaboration with colleagues at the California Institute of Technology, the FMI neurobiologists went on to show that one of the cell types produces a signaling protein known as protein kinase C delta. This has provided the researchers with a marker for cells in the amygdala which directly regulate the expression of fear. They can now manipulate and study the behavior of these cells under a variety of conditions. Commenting on the relevance of their findings, FMI Group Leader Andreas L-thi, who led the study, said: "We now have at our disposal a molecular tool which should allow us to gain a better understanding of processes in the amygdala - and also of phobias and post-traumatic stress disorders."

Lastly, the studies also revealed that these circuits play an important role in the generalization of fear. The same neurons are involved when fear becomes divorced from the original situation and becomes increasingly general. This may mean, for example, that some people's feelings of claustrophobia in an elevator will develop into a fear of crowds and, finally, fear of leaving the house. Patients with disorders of this kind live in a state of constant anxiety, which remains difficult to treat.

For decades, the function of nerve cells has been studied with the aid of electrophysiological methods, which allow neural excitation to be measured in a particular region of the brain. Over the last few years, this method has increasingly been combined with newer, more powerful approaches. With so-called optogenetic methods, neurons can be stimulated selectively, rapidly and reversibly. This involves the use of light-sensitive membrane proteins from algae, such as channelrhodopsin, which are stimulated by light so as to activate neurons. Membrane proteins can be produced in selected neurons or selected neural circuits, making it possible to study clearly defined individual neurons. At the FMI, optogenetic approaches are being exploited and continuously refined by a number of neurobiology research groups. As well as being used in the work described above, this method has enabled FMI scientists to gain new insights into visual and olfactory processes.