The Bed Nucleus of the Stria Terminalis Mediates Inter-individual Variations in Anxiety and Fear

Abstract

While learning to fear stimuli that predict danger promotes survival, the inability to inhibit fear to inappropriate cues leads to a pernicious cycle of avoidance behaviors. Previous studies have revealed large inter-individual variations in fear responding with clinically anxious humans exhibiting a tendency to generalize learned fear to safe stimuli or situations. To shed light on the origin of these inter-individual variations, we subjected rats to a differential auditory fear conditioning paradigm in which one conditioned auditory stimulus (CSϩ) was paired to footshocks whereas a second (CSϪ) was not. We compared the behavior of rats that received pretraining excitotoxic lesions of the bed nucleus of the stria terminalis (BNST) to that of sham rats. Sham rats exhibit a continuum of anxious/fearful behaviors. At one end of the continuum were rats that displayed a poor ability to discriminate between the CSϩ and CSϪ, high contextual freezing, and an anxiety-like trait in the elevated plus maze (EPM). At the other end were rats that display less fear generalization to the CSϪ, lower freezing to context, and a nonanxious trait in the EPM. Although BNST-lesioned rats acquired similarly high levels of conditioned fear to the CSϩ, they froze less than sham rats to the CSϪ. In fact, BNST-lesioned rats behaved like sham rats with high discriminative abilities in that they exhibited low contextual fear and a nonanxious phenotype in the EPM. Overall, this suggests that inter-individual variations in fear generalization and anxiety phenotype are determined by BNST influences on the amygdala and/or its targets.

Adenosine A2A Receptors in the Amygdala Control Synaptic Plasticity and Contextual Fear Memory

“…In fact, several studies have dissected the involvement of different brain regions in the processing of contextual and cued fear memory (Orsini and Maren, 2012), albeit the expression of both forms of contextual fear mostly depend on amygdala circuits (Goosens and Maren, 2001). This is heralded by the differential impact on cued and contextual fear memory upon manipulation of different molecular targets (eg, Sui et al, 2006;Burghart and Bauer, 2013) or lesions/inactivation (eg, Duvarci et al, 2009;Baldi et al, 2013) in different brain regions. This apparent different involvement of A 2A Rs in the amygdala and in other brain regions in the acquisition and expression of contextual fear, which still remains to be detailed, does not undermine the key impact of A 2A R blockade in long-term contextual fear, a conclusion of particular importance in view of the prominent role of contextualization in behavioral flexibility and psychopathology (reviewed in Maren et al, 2013).…”

Genetic Strain Differences in Learned Fear Inhibition Associated with Variation in Neuroendocrine, Autonomic, and Amygdala Dendritic Phenotypes

“…For example, there are a number of rodent models in which a specific rat or mouse strain (Cohen et al, 2008), sub-population (Duvarci et al, 2009), or selectively bred line (Muigg et al, 2008) exhibits features consistent with inherent susceptibility to excessive fear after an experimental trauma such as Pavlovian fear conditioning. Along these lines, we recently identified an inbred mouse strain, 129S1/SvImJ (S1), which displays a profound deficit in cued fear extinction, coupled with functional abnormalities in corticoamygdala circuitry mediating extinction (Camp et al, 2009;Hefner et al, 2008;Whittle et al, 2010).…”

Sleep sharpens sensory stimulus coding in human visual cortex after fear conditioning

“…electrical shock) through associative Pavlovian conditioning can subsequently shift the tuning curves of neurons in sensory cortices towards the characteristic sensory features of the conditioned stimulus and/or increase the number of neurons representing that stimulus (Gdalyahu et al, 2012;Resnik et al, 2011;Weinberger, 2004Weinberger, , 2007. Such remodeling of sensory representations may critically depend on modulatory signals from the amygdala (Armony et al, 1997;Chavez et al, 2009;Duvarci et al, 2009;Shaban et al, 2006). Likewise, in humans, Li et al (2008) showed that initially indistinguishable odors (mirror-image molecules) can be transformed into discriminable percepts after aversive conditioning, associated with distinctive activations in the olfactory cortex as demonstrated by functional Magnetic Resonance Imaging (fMRI).…”