Journal Article

Amygdala intercalated neurons are required for expression of fear extinction

Paré, Denis, Fidacaro, George A., Likhtik, Ekaterina, Apergis-Schoute, John, Popa, Daniela

2008

Overview

Tripping the 'fear switch' For many animals, an ability to switch from a 'normal' bold or exploratory approach to a situation to a more defensive approach when prudent is an important survival aid. Much is known about the role of entire brain areas in such processes, but what happens at the level of neuronal circuits is less well understood. 'Fear extinction' and 'renewal', two processes in which learned fearful responses to stimuli associated with unpleasant consequences are unlearned, then renewed, are effective models for probing mechanisms associated with changes in behavioural state. Herry et al . show that changes in the balance of activity of two distinct neuronal populations in the basolateral amygdala can trigger transitions between states of high and low fear in mice. Likhtik et al . report another mechanism for 'unlearning' fearful memories, this time in rats. Amygdala cells known as intercalated neurons, which receive information from the basolateral amygdala, appear to be responsible in this case. This work suggests possible new avenues for the treatment of anxiety disorders. Although fearful responses to stimuli associated with unpleasant consequences are quickly learned, they can also be unlearned. This unlearning process, called 'extinction', is thought to depend on plastic changes in the amygdala. A specific population of amygdala cells (intercalated neurons) that are responsible for this unlearning have been pinpointed. Selective destruction of this cell type with a toxin leads to a corresponding decrease in the extinction of learned fear memories. Congruent findings from studies of fear learning in animals and humans indicate that research on the circuits mediating fear constitutes our best hope of understanding human anxiety disorders 1 , 2 , 3 , 4 . In mammals, repeated presentations of a conditioned stimulus that was previously paired to a noxious stimulus leads to the gradual disappearance of conditioned fear responses. Although much evidence suggests that this extinction process depends on plastic events in the amygdala 1 , 2 , 3 , 4 , 5 , 6 , 7 , the underlying mechanisms remain unclear. Intercalated (ITC) amygdala neurons constitute probable mediators of extinction because they receive information about the conditioned stimulus from the basolateral amygdala (BLA) 8 , 9 , and contribute inhibitory projections to the central nucleus (CEA) 10 , 11 , the main output station of the amygdala for conditioned fear responses 12 . Thus, after extinction training, ITC cells could reduce the impact of conditioned-stimulus-related BLA inputs to the CEA by means of feed-forward inhibition. Here we test the hypothesis that ITC neurons mediate extinction by lesioning them with a toxin that selectively targets cells expressing µ-opioid receptors (µORs). Electron microscopic observations revealed that the incidence of µOR-immunoreactive synapses is much higher in ITC cell clusters than in the BLA or CEA and that µORs typically have a post-synaptic location in ITC cells. In keeping with this, bilateral infusions of the µOR agonist dermorphin conjugated to the toxin saporin in the vicinity of ITC neurons caused a 34% reduction in the number of ITC cells but no significant cell loss in surrounding nuclei. Moreover, ITC lesions caused a marked deficit in the expression of extinction that correlated negatively with the number of surviving ITC neurons but not CEA cells. Because ITC cells exhibit an unusual pattern of receptor expression, these findings open new avenues for the treatment of anxiety disorders.

• Publisher: Nature Publishing Group UK,Nature Publishing,Nature Publishing Group
• Subject: Amygdala (Brain) / Amygdala - cytology / Amygdala - physiology / Amygdala - ultrastructure / Anatomical correlates of behavior / Animals / Behavioral psychophysiology / Biological and medical sciences / Cells / Conditioning, Psychological - physiology / Electron microscopes / Endangered & extinct species / Extinction, Psychological - physiology / Fear / Fear - physiology / Freezing Reaction, Cataleptic - drug effects / Freezing Reaction, Cataleptic - physiology / Fundamental and applied biological sciences. Psychology / Humanities and Social Sciences / Immunotoxins - pharmacology / Interneurons - cytology / Interneurons - drug effects / Interneurons - physiology / Interneurons - ultrastructure / Laboratory animals / letter / multidisciplinary / Neurons / Psychology. Psychoanalysis. Psychiatry / Psychology. Psychophysiology / Rats / Rats, Sprague-Dawley / Receptors, Opioid - drug effects / Receptors, Opioid - metabolism / Ribosome Inactivating Proteins, Type 1 - pharmacology / Saporins / Science / Science (multidisciplinary) / Species extinction / Toxins