Diverging neural pathways assemble a behavioural state from separable features in anxiety

Abstract

Different subregions of the bed nucleus of the stria terminalis are shown to increase and decrease anxiety in mice, and distinct neural projections arising from a single coordinating brain region modulate different anxiety features. The bed nucleus of the stria terminalis (BNST), a brain area involved in fear and anxiety, also projects into brain areas with contrasting roles, including some involved in the reward response. Two papers now dissect out the functional properties of various subregions of projections of BNST in mice. Garret Stuber and colleagues examine BNST projections to the ventral tegmental area and find that glutamatergic and GABAergic projections have opposing effects on reward and aversion. Karl Deisseroth and colleagues find that different subregions of BNST increase and decrease anxiety, and that distinct projections modulate different features of anxiety. This work suggests that anxiety arises not from a single neural circuit, but from the interplay between anxiety-producing and anxiety-reducing circuits. Behavioural states in mammals, such as the anxious state, are characterized by several features that are coordinately regulated by diverse nervous system outputs, ranging from behavioural choice patterns to changes in physiology (in anxiety, exemplified respectively by risk-avoidance and respiratory rate alterations)1,2. Here we investigate if and how defined neural projections arising from a single coordinating brain region in mice could mediate diverse features of anxiety. Integrating behavioural assays, in vivo and in vitro electrophysiology, respiratory physiology and optogenetics, we identify a surprising new role for the bed nucleus of the stria terminalis (BNST) in the coordinated modulation of diverse anxiety features. First, two BNST subregions were unexpectedly found to exert opposite effects on the anxious state: oval BNST activity promoted several independent anxious state features, whereas anterodorsal BNST-associated activity exerted anxiolytic influence for the same features. Notably, we found that three distinct anterodorsal BNST efferent projections—to the lateral hypothalamus, parabrachial nucleus and ventral tegmental area—each implemented an independent feature of anxiolysis: reduced risk-avoidance, reduced respiratory rate, and increased positive valence, respectively. Furthermore, selective inhibition of corresponding circuit elements in freely moving mice showed opposing behavioural effects compared with excitation, and in vivo recordings during free behaviour showed native spiking patterns in anterodorsal BNST neurons that differentiated safe and anxiogenic environments. These results demonstrate that distinct BNST subregions exert opposite effects in modulating anxiety, establish separable anxiolytic roles for different anterodorsal BNST projections, and illustrate circuit mechanisms underlying selection of features for the assembly of the anxious state.