"The human subjects in South-Africa: a globally unique population.
The group of human subjects that participated to this study suffer from Urbach Wiethe disease (UWD), an extremely rare genetic condition. In the Northern Cape of South Africa, however, it has spread as a result of a founder effect after introduction of a genetic mutation by European settlers 400 years ago. These UWD patients exhibit selective damage of a restricted part of brain called Basolateral amygdala (BLA), located in the temporal lobe. The adjacent brain region, the Central amygdala (CeA), which triggers different expressions of fear (freezing, potentiated startle, physiological changes), is intact. Thus, this is a unique occasion to assess a new function of the human BLA. Contrary to the previous UWD case, we found that these UWD subjects did not exhibit decreased fear, but instead increased fear responses, particularly when facing an escapable threat. This suggested an inhibitory control of the BLA over passive fear responses that are triggered by the CeA, and that becomes active when preparing to escape from threat.
A new cross-species mechanism for actively controlling fear.
To expose this precise mechanism, we 1) developed in parallel a rat model in which we inhibited the BLA with a recent technology, called chemogenetic, and 2) designed for both human subjects and rats an equivalent ""escape from threat"" task. We then assessed central amygdala output to the brainstem by measuring in rats freezing, a common animal reaction facing feargul stimuli, and both in rats and humans potentiated startle responses, a reflex conserved between humans and rodents. These measures are considered most direct readouts of passive responses to threats. In both species loss of BLA function increased these responses, and was accompanied, in rats, by a decrease in active escape from threat. In the UWD group this increased central amygdala output could also be measured by fMRI of the CeA and pons.
To assess the pathway through which the BLA controls output from the central amygdala to the brainstem we studied a local inhibitory pathway within the CeA that we had previously revealed to be oxytocin-sensitive. We found that its activation by oxytocin could fully recover the changes in freezing, startle and escape response caused by BLA inhibition. This thereby provides a new interpretation of our previous data that had shown decreased freezing by oxytocin without affecting physiological expression of fear. Thus, oxytocin appears to prepare the rat for escape, by actively facing the threat. Taken together, we identified a novel mechanism through which the BLA inhibits passive fear responses when the individual is offered the possibility to escape: It involves BLA activation of inhibitory neurons in the CeA that are sensitive to oxytocin.
Impact of the study.
1. Animal-human translation researchers
Our data reveal how the BLA, via the CeA, adaptively regulates escape behavior from imminent threat and that this mechanism is evolutionary conserved across rodents and humans. Putting an animal model side-by-side these human findings represents a rather unique combination of two fields, which we hope may push the boundaries for innovative translational research.
2. Human emotion and clinical researchers: The BLA in humans compared to rodents has undergone an expansion in size relative to other amygdala subregions that is huge and it may have gained additional functions to similar extent. We feel, in fact, we are only at the beginning of starting to explore the rich repertoire of changes in emotional and motivational behavior that is present in these BLA-damaged human subjects. The brain mechanism we explored, and specifically the pharmacological activation method employed, opens up new opportunities for the study and potential treatment of fear and anxiety disorders.
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