Neurobiology of fear and specific phobias

Abstract

Fear, which can be expressed innately or after conditioning, is triggered when a danger or a stimulus predicting immediate danger is perceived. Its role is to prepare the body to face this danger. However, dysfunction in fear processing can lead to psychiatric disorders in which fear outweighs the danger or possibility of harm. Although recognized as highly debilitating, pathological fear remains insufficiently treated, indicating the importance of research on fear processing. The neurobiological basis of normal and pathological fear reactions is reviewed in this article. Innate and learned fear mechanisms, particularly those involving the amygdala, are considered. These fear mechanisms are also distinguished in specific phobias, which can indeed be nonexperiential (implicating innate, learning-independent mechanisms) or experiential (implicating learning-dependent mechanisms). Poor habituation and poor extinction are presented as dysfunctional mechanisms contributing to persistence of nonexperiential and experiential phobias, respectively.

Figure 1.

Interactions between glucocorticoids and norepinephrine (NA) in the regulation of GABAergic activity. During stress, adrenal hormones, epinephrine, and glucocorticoids, are released. Epinephrine, which does not cross the blood-brain barrier, induces the release of NA in the basolateral amygdala (BLA) by activating vagal afferents to the nucleus of the solitary tract (NTS). NA neurons in the NTS send direct noradrenergic fibers to the BLA. NA neurons from the NTS project also to the locus coeruleus (LC), which noradrenergic fibers reach directly the BLA. Glucocorticoids freely cross the blood–brain barrier and potentiate NA release in the BLA and facilitate the NA inhibitory effect on GABA interneurons in the BLA (de Quervain et al. 2009). This results in the decrease of excitability threshold of the pyramidal neurons in the BLA, which release the excitatory neurotransmitter, glutamate (Glu), in the central amygdala (CeA).

Figure 2.

Interactions between serotonin (5-HT) and GABAergic systems in the basolateral amygdala (BLA) during fear expression and extinction. Following fear conditioning, presentation of the conditioned cue activates glutamatergic (Glu) neurons in the lateral amygdala (LA) that project to fear neurons (F) in the basolateral amygdala (BLA). The fear neurons activate, in turn, neurons in the central amygdala (CeA) for fear expression. The LA neurons also activate a BLA cell population that expresses cholecystokinin (CCK) and establishes GABAergic synapses with extinction neurons (E) within the BLA, inhibiting therefore these extinction neurons. Consequently, extinction neurons cannot inhibit fear expression through their Glu projections to BLA interneurons containing parvalbumin (PV), which establish a GABAergic connection with the fear neurons, or through their Glu projections to intercalated cells (ITC), which send GABAergic fibers to the CeA. It is well known that endocannabinoid signaling results in retrograde inhibition of afferent neurotransmission. Interestingly, the cannabinoid type 1 receptors are located presynaptically on CCK-containing cells. However, endocannabinoid synthesis is initiated via voltage-dependent mechanisms (Kano et al. 2009) and because of the inhibitory effect of CCK-containing cells on extinction neurons, endocannabinoids are not released. Here, it is hypothesized that, during extinction training, repeated presentations of the conditioned stimulus alone, indicating safety, may induce progressive enhancement of serotonin (5-HT) release in the BLA, which may partially activate the extinction neurons, hence provoking the release of endocannabinoids. The activation of the extinction neurons may be achieved with the inhibitory effect of endocannabinoids on CCK-containing cells via their cannabinoid type 1 receptors, resulting in inhibition of fear expression.