An integrative review of attention biases and their contribution to treatment for anxiety disorders

Models of exposure therapy, one of the key components of cognitive behavioral therapy for anxiety disorders, suggest that attention may play an important role in the extinction of fear and anxiety. Evidence from cognitive research suggests that individual differences may play a causal role in the onset and maintenance of anxiety disorders and so it is also likely to influence treatment. We review the evidence concerning attention and treatment outcomes in anxiety disorders. The evidence reviewed here suggests that that attention biases assessed at pre-treatment might actually predict improved response to treatment, and in particular that prolonged engagement with threat as measured in tasks such as the dot probe is associated with greater reductions in anxious symptoms following treatment. We examine this research within a fear learning framework, considering the possible role of individual differences in attention in the extinction of fear during exposure. Theoretical, experimental and clinical implications are discussed, particularly with reference to the potential for attention bias modification programs in augmenting treatment, and also with reference to how existing research in this area might inform best practice for clinicians.published_or_final_versio

The role of stimulus specificity and attention in the generalization of extinction

Exposure therapy for anxiety is effective but fear can still return afterward. This may be because the stimuli that people are exposed to are dissimilar from the stimuli to which fear was originally acquired. After pairing an animal-like image (A) with a shock stimulus (US), a perceptually similar stimulus (B) was presented without the US in extinction. Participants were then shown A (ABA), a second generalization stimulus (ABC) or B (ABB). Groups ABA and ABC evidenced a return of US expectancy relative to participants who were shown B (ABB). Participants in group ABC who self-reported high levels of attentional control evidenced greater return of expectancy relative to participants low in attentional control. Participants with a high level of attentional control also showed steeper extinction gradients. Attentional control may influence perceptions of similarity and the learning that follows. Making note of such differences may be valuable in exposure treatment for anxiety.postprin

Basal ryanodine receptor activity suppresses autophagic flux

The inositol 1,4,5-trisphosphate receptors (IP3Rs) and intracellular Ca2+ signaling are critically involved in regulating different steps of autophagy, a lysosomal degradation pathway. The ryanodine receptors (RyR), intracellular Ca2+-release channels mainly expressed in excitable cell types including muscle and neurons, have however not yet been extensively studied in relation to autophagy. Yet, aberrant expression and excessive activity of RyRs in these tissues has been implicated in the onset of several diseases including Alzheimer’s disease, where impaired autophagy regulation contributes to the pathology. In this study, we determined whether pharmacological RyR inhibition could modulate autophagic flux in ectopic RyR-expressing models, like HEK293 cells and in cell types that endogenously express RyRs, like C2C12 myoblasts and primary hippocampal neurons. Importantly, RyR3 overexpression in HEK293 cells impaired the autophagic flux. Conversely, in all cell models tested, pharmacological inhibition of endogenous or ectopically expressed RyRs, using dantrolene or ryanodine, augmented autophagic flux by increasing lysosomal turn-over (number of autophagosomes and autolysosomes measured as mCherry-LC3 punctae/cell increased from 70.37 ± 7.81 in control HEK RyR3 cells to 111.18 ± 7.72 and 98.14 ± 7.31 after dantrolene and ryanodine treatments, respectively). Moreover, in differentiated C2C12 cells, transmission electron microscopy demonstrated that dantrolene treatment decreased the number of early autophagic vacuoles from 5.9 ± 2.97 to 1.8 ± 1.03 per cellular cross section. The modulation of the autophagic flux could be linked to the functional inhibition of RyR channels as both RyR inhibitors efficiently diminished the number of cells showing spontaneous RyR3 activity in the HEK293 cell model (from 41.14% ± 2.12 in control cells to 18.70% ± 2.25 and 9.74% ± 2.67 after dantrolene and ryanodine treatments, respectively). In conclusion, basal RyR-mediated Ca2+-release events suppress autophagic flux at the level of the lysosomes

Ryanodine receptors are targeted by anti-apoptotic Bcl-X-L involving its BH4 domain and Lys87 from its BH3 domain

Anti-apoptotic B-cell lymphoma 2 (Bcl-2) family members target several intracellular Ca2+-transport systems. Bcl-2, via its N-terminal Bcl-2 homology (BH) 4 domain, inhibits both inositol 1,4,5-trisphosphate receptors (IP(3)Rs) and ryanodine receptors (RyRs), while Bcl-X-L, likely independently of its BH4 domain, sensitizes IP3Rs. It remains elusive whether Bcl-XL can also target and modulate RyRs. Here, Bcl-X-L co-immunoprecipitated with RyR3 expressed in HEK293 cells. Mammalian protein-protein interaction trap (MAPPIT) and surface plasmon resonance (SPR) showed that Bcl-XL bound to the central domain of RyR3 via its BH4 domain, although to a lesser extent compared to the BH4 domain of Bcl-2. Consistent with the ability of the BH4 domain of Bcl-X-L to bind to RyRs, loading the BH4-Bcl-X-L peptide into RyR3-overexpressing HEK293 cells or in rat hippocampal neurons suppressed RyR-mediated Ca2+ release. In silico superposition of the 3D-structures of Bcl-2 and Bcl-XL indicated that Lys87 of the BH3 domain of Bcl-XL could be important for interacting with RyRs. In contrast to Bcl-X-L, the Bcl-X-L(K87D) mutant displayed lower binding affinity for RyR3 and a reduced inhibition of RyR-mediated Ca2+ release. These data suggest that Bcl-X-L binds to RyR channels via its BH4 domain, but also its BH3 domain, more specific Lys87, contributes to the interaction

A learning theory of attachment: Unraveling the black box of attachment development

Attachment is an inborn behavioral system that is biologically driven and essential for survival. During child development, individual differences in (in)secure attachment emerge. The development of different attachment behaviors has been traditionally explained as a process during which experiences with (lack of) responsive and supportive care are internalized into working models of attachment. However, this idea has been criticized for being vague and even untestable. With the aim of unraveling this black box, we propose to integrate evidence from conditioning research with attachment theory to formulate a Learning Theory of Attachment. In this review, we explain how the development of individual differences in attachment security at least partly follows the principles of classical and operant conditioning. We combine observed associations between attachment and neurocognitive and endocrinological (cortisol, oxytocin, and dopamine) processes with insights in conditioning dynamics to explain the development of attachment. This may contribute to the explanation of empirical observations in attachment research that are insufficiently accounted for by traditional attachment theory