A midbrain dynorphin circuit promotes threat generalization.
A midbrain dynorphin circuit promotes threat generalization.
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DOI：
10.1016/j.cub.2021.07.047
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发表时间：
2021-10-11
期刊：
影响因子：
--
通讯作者：
Zweifel LS
中科院分区：
文献类型：
--
作者：
Fellinger L;Jo YS;Hunker AC;Soden ME;Elum J;Juarez B;Zweifel LS
随着威胁强度的增加，预测性和非预测性威胁刺激之间的区别逐渐减弱。调解从歧视性威胁反应向广义威胁反应过渡的核心机制仍然没有得到很好的解决。在这里，我们确定了应激和烦躁相关的kappa阿片受体（KOR）及其配体dynorphin (Dyn)，作用于腹侧被皮层（VTA），作为调节威胁泛化的关键底物。我们确定了几个对VTA的失啡能输入，并证明了来自终纹床核（BNST）和中缝背核（DRN）的投射都有助于焦虑样行为，但对威胁概括的影响不同。这些数据表明，条件威胁识别与威胁强度呈倒“U”型关系，并建立了中脑KOR/Dyn信号促进威胁泛化的作用。Fellinger等人的研究表明，恐惧歧视与非条件刺激强度呈倒“U”型关系，这取决于kappa阿片受体。他们表明，多巴胺神经元上的kappa是必要的，并确定了从中缝背的表达前啡肽的神经元到腹侧被盖的回路，该回路驱动了这种效应。
Discrimination between predictive and non-predictive threat stimuli decreases as threat intensity increases. The central mechanisms that mediate the transition from discriminatory to generalized threat responding remain poorly resolved. Here, we identify the stress- and dysphoria-associated kappa opioid receptor (KOR) and its ligand dynorphin (Dyn), acting in the ventral tegmental area (VTA), as a key substrate for regulating threat generalization. We identify several dynorphinergic inputs to the VTA and demonstrate that projections from the bed nucleus of the stria terminalis (BNST) and dorsal raphe nucleus (DRN) both contribute to anxiety-like behavior but differentially affect threat generalization. These data demonstrate that conditioned threat discrimination has an inverted ‘U’ relationship with threat intensity and establish a role for KOR/Dyn signaling in the midbrain for promoting threat generalization. Fellinger et al., show that fear discrimination has an inverted ‘U’ relationship with unconditioned stimulus intensity that depends on kappa opioid receptors. They show that kappa on dopamine neurons are necessary and identify a circuit from prodynorphin expressing neurons in the dorsal raphe to the ventral tegmental that drive this effect.
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影响因子：
7.4
作者：
Carlezon WA Jr;Krystal AD
通讯作者：
Krystal AD
影响因子：
11
作者：
De Bundel, D.;Zussy, C.;Espallergues, J.;Gerfen, C. R.;Girault, J-A;Valjent, E.
通讯作者：
Valjent, E.
影响因子：
--
作者：
Gore, Bryan B;Soden, Marta E;Zweifel, Larry S
通讯作者：
Zweifel, Larry S
DOI：
10.1073/pnas.0603081103
发表时间：
2006-06-06
影响因子：
11.1
作者：
Hnasko, Thomas S.;Perez, Francisco A.;Palmiter, Richard D.
通讯作者：
Palmiter, Richard D.
影响因子：
5.3
作者：
Ford, CP;Mark, GP;Williams, JT
通讯作者：
Williams, JT