Responses to aversive stimuli can shift from a quickly developing and rapidly dissipating state of fear to a long-lasting anxious apprehension, largely depending on the physical or psychological distance to threat. The balance of these states are critical variables relating to anxiety sensitivity and anxiety disorders. These variables are controlled by synaptic circuits of the extended amygdala, comprising an array of connected brain nuclei containing the bed nucleus of the stria terminalis (BNST). By combining electrophysiology/optogenetics and molecular genetics, we use cell-type and pathway-specific rescue and deletion approaches, for characterization of distinct pathways from amygdala to BNST, and for identification of types of neurons and synaptic circuits within and across BNST subregions, and we combine these approaches with dedicated behavioural training paradigms. Results allow causal interpretations to be drawn on mechanisms mediating the individual fear profile during anticipation or presence of a discrete or distant threat, during fear extinction, or late fear return. Our results thereby identify biosignatures contributing to the shift from physiological to pathological states of fear and anxiety.
Signalling by neuropeptide Y receptors (Y2R) in BNST micro-circuits and relevance for late return of fear. Cannelrhodopsin (ChR2)-assisted “paired” patch-clamp recordings in BNST ex vivo from Y2lox/lox mice (A-C) show Y2R-modulation of GABAergic responses in synaptically coupled neurons that is absent after Cre-mediated Y2R deletion (E), and that prevents late return of fear after extinction in vivo (F). Black and blue traces/symbols represent control and Y2R deletion, respectively. Y2R agonist (PYY3-36). see Bartsch et al., Mol Psych 2020