A new GABAergic projection from the BNST onto accumbal parvalbumin neurons controls anxiety

Abstract

1The prevailing view is that parvalbumin (PV) interneurons play modulatory 2 roles in emotional response through local medium spiny projection neurons 3 (MSNs). Here, we show that PV activity within the nucleus accumbens shell 4 (sNAc) is required for producing anxiety-related avoidance when mice are 5 under anxiogenic situations; sNAc PV neurons exhibited high excitability in 6 chronically stressed mice model, which generated excessive maladaptive 7 avoidance behavior in an anxiogenic context. We also discovered a novel 8 GABAergic projections from the anterior dorsal bed nuclei of stria terminalis 9 (adBNST) to sNAc PV neurons; optogenetic activation of these afferent 10 terminals in sNAc produced an anxiolytic effect via GABA transmission. Next, 11 we further demonstrated that chronic stressors attenuated the inhibitory 12 synaptic transmission at adBNST GABA sNAc PV synapses, which in turn 13 explains the hyperexcitability of sNAc PV neurons on stressed models; therefore, 14 activation of these GABAergic afferents in sNAc rescued the excessive 15 avoidance behavior related to anxious state. 16Our findings reveal the coordination between BNST and NAc through an 17 inhibitory architecture in controlling of anxiety-related response and provide a 18 neurobiological basis for therapeutic interventions in pathological anxiety. 19 Introduction 1 Stressors and stress responses are critical for guiding both approach and 2 avoidance behaviors in animals and humans. Exposure to chronic, 3 unpredictable stressors leads to increased anxiety responses, including 4 excessive avoidance behavior, and this exposure has been adopted to study 5 anxious state-related behaviors 1, 2 . The bed nucleus of the stria terminalis 6 (BNST), a subregion of the extended amygdala, is a critical node in the stress 7 response 3, 4 . Recent work on human drug addiction has also demonstrated a 8 role of BNST in withdrawal-related anxiety and relapse, indicating an intrinsic 9 link between this stress response region and the reward system. The nucleus 10 accumbens (NAc) is a vital component in the reward circuitry 5-7 , which 11 responds to stress signals 8, 9 and has a dominant effect on anxiety regulation 10 . 12 However, with the exception of one 15-year-old anatomical observation 11 , the 13 connectivity between NAc and BNST, and whether it is necessary in producing 14 anxiety-related behavior, remains unexplored. Furthermore, GABAergic 15 efferents originating from the BNST are predominantly sent downstream 12, 13 ; 16 however, the nature and function of any GABAergic input to NAc is unknown.17 Medium spiny neurons that express dopamine 1 and 2 receptors (D1-and 18 D2-MSNs) are the predominant neural population in the NAc . Regarding 19 anxiety regulation, it is accepted that D1-MSNs are not involved in 20 anxiety-related behavior, but play roles in modulating reward-related 21 responses 14, 15 whereas D2-MSNs may regulate anxiety-related aversion or avoidance behavior 16 . However, the role of D2-MSNs are not entirely clear 1 because ot...