Data_Sheet_1_Dorsal Bed Nucleus of the Stria Terminalis-Subcortical Output Circuits Encode Positive Bias in Pavlovian Fear and Reward.pdf

Opposite emotions like fear and reward states often utilize the same brain regions. The bed nucleus of the stria terminalis (BNST) comprises one hub for processing fear and reward processes. However, it remains unknown how dorsal BNST (dBNST) circuits process these antagonistic behaviors. Here, we exploited a combined Pavlovian fear and reward conditioning task that exposed mice to conditioned tone stimuli (CS)s, either paired with sucrose delivery or footshock unconditioned stimuli (US). Pharmacological inactivation identified the dorsal BNST as a crucial element for both fear and reward behavior. Deep brain calcium imaging revealed opposite roles of two distinct dBNST neuronal output pathways to the periaqueductal gray (PAG) or paraventricular hypothalamus (PVH). dBNST neural activity profiles differentially process valence and Pavlovian behavior components: dBNST-PAG neurons encode fear CS, whereas dBNST-PVH neurons encode reward responding. Optogenetic activation of BNST-PVH neurons increased reward seeking, whereas dBNST-PAG neurons attenuated freezing. Thus, dBNST-PVH or dBNST-PAG circuitry encodes oppositely valenced fear and reward states, while simultaneously triggering an overall positive affective response bias (increased reward seeking while reducing fear responses). We speculate that this mechanism amplifies reward responding and suppresses fear responses linked to BNST dysfunction in stress and addictive behaviors.

对立情绪如恐惧与奖赏状态往往激活相同的脑区。床核终纹区（BNST）构成了处理恐惧与奖赏过程的一个枢纽。然而，背侧BNST（dBNST）回路如何处理这些拮抗行为尚属未知。本研究中，我们利用了一种结合了巴甫洛夫式恐惧与奖赏条件反射任务，将小鼠暴露于条件性声音刺激（CS），这些刺激要么与蔗糖的给予相匹配，要么与无条件的足部电击刺激（US）相结合。药理学失活研究揭示了背侧BNST对于恐惧与奖赏行为均至关重要。深度脑钙成像揭示了两个不同的dBNST神经元输出通路对导水管周围灰质（PAG）或室旁核（PVH）的作用相反。dBNST的神经活动模式在处理价值感和巴甫洛夫行为成分方面存在差异：dBNST-PAG神经元编码恐惧CS，而dBNST-PVH神经元编码奖赏反应。光遗传学激活BNST-PVH神经元增强了奖赏寻求，而dBNST-PAG神经元则减轻了僵化反应。因此，dBNST-PVH或dBNST-PAG回路编码了具有相反价值的恐惧与奖赏状态，同时触发了一种整体积极情感反应偏向（增加奖赏寻求，降低恐惧反应）。我们推测，这一机制放大了与BNST功能障碍相关的奖赏反应，并抑制了与压力和成瘾行为相关的恐惧反应。