Neuronal circuits involved in acquisition and control of behavioural fear responses identified

Fear is an adaptive response, essential to the survival of many species. This behavioural adaptation may be innate but can also be a consequence of conditioning, during the course of which an animal learns that a particular stimulus precedes an unpleasant event. There is a large amount of data indicating that the amygdala, a particular structure in the brain, is strongly involved during the learning of "conditioned" fear. However, until now, the underlying neuronal circuits have remained largely unknown. Now, research involving several Swiss and German teams and a researcher from Inserm Unit 862, "Neurocentre Magendie", in Bordeaux, has been able to identify, for the first time, distinct neuronal circuits within the central nucleus of the amygdala which are specifically involved in acquisition and control of behavioural fear responses. Details of these results are published in this week's edition of the journal Nature.

In this study, laboratory mice were first subjected to a simple behavioural task which consisted of learning that an audible stimulus presaged the arrival of an unpleasant event. Following this conditioning, presentation of the audible stimulus induced a set of behavioural manifestations of fear such as freezing of the animals. Using highly innovative pharmacological and optogenetic techniques, the researchers have shown that the medial and central nuclei of the central amygdala were differentially involved in either learning or behavioural manifestation of fear responses (see the diagram on the next page). Indeed, the researchers were able to show that after inactivating the lateral subdivision of the central nucleus of the amygdala, the animals no longer learnt the association between the sound and the unpleasant event. By contrast, inactivation of the medial subdivision of this nucleus did not disrupt the learning of fear; however, the animals were now no longer able to give a behavioural manifestation to their fear, i.e. freezing.

In that second step, real-time recording of the activity of the neurons in the lateral and medial subdivisions of the central amygdala, using unique electrophysiological techniques, made it possible for the researchers to identify the specific neurons, within the structures, which were involved in conditioning and behavioural manifestation of fear responses.

These neurons are inhibitor cells belonging to very organized and strongly interconnected neuronal circuits. Modification of the activity of these circuits enables the relevant behavioural fear response to be selected as a function of the environmental situation.

Hence, our work defines the functional architecture of the neuronal circuits of the central amygdala and their role in acquisition and regulation of fear behaviours. Precise identification of the neuronal circuits which control fear is a major clinical challenge. Patients suffering from disorders, such as post-traumatic stress disorder or anxiety problems, exhibit disruption of certain neuronal circuits which leads to unsuitable anxiety behaviour responses. The selective manipulation of neuronal circuits that we have identified, using new therapeutic approaches which need to be developed further, could make it possible to regulate the pathological manifestations of fear in these patients.