两篇Nature提出新观点：焦虑的来源

焦虑，这是一个我们熟知的名词，而且我们大家也都有可能经历过焦虑，比如在等待上司公布升职的时候，或者当医生即将宣布诊断结果的时候。关于焦虑的一些重要问题，如焦虑状态的不同组成部分如何组织在一起，如何在神经回路中表现出，至今科学家们了解的并不清楚……

　　生物通报道：焦虑，这是一个我们熟知的名词，而且我们大家也都有可能经历过焦虑，比如在等待上司公布升职的时候，或者当医生即将宣布诊断结果的时候。这种弥散着不安的心情，有时还会伴随有出汗和呼吸的微妙变化。

焦虑的出现与生活环境有关，不过也有可能无缘无故就发生焦虑。这种情况应该总体来说是健康并具有适应性的，不过据一项来自美国的调查显示，对于大约有三分之一的人来说，生活中产生的焦虑会造成人体衰弱。

关于焦虑的一些重要问题，如焦虑状态的不同组成部分如何组织在一起，如何在神经回路中表现出，至今科学家们了解的并不清楚。在最新一期（3月21日）的Nature杂志上，两个研究组分别就此作出了解答，分别公布在两篇Nature文章中。

这两个研究组采用了光遗传学的方法对小鼠不同神经细胞亚群进行了分析，剖析了不同细胞群体协同作用，共同完成焦虑神经发生的作用机制。

研究对象是称为终纹床核（bed nucleus of the stria terminalis，BNST）的弥漫性脑区。之前的研究发现BNST病变能减少焦虑，和对某些环境的恐惧感，并认为这一区域与几个参与动机行为和应激反应的其它大脑区域有关，但是对于各种BNST亚群和次区域的功能，以及这些连接的意义，研究人员仍然不清楚。

第一项研究中，Jennings和他的同事们聚焦于腹面BNST（vBNST）在介导焦虑，和调控动机行为中的作用，动机行为伴随着其它行为，可能受到焦虑的调节。

之前研究认为vBNST包含了功能不同的细胞群，最新研究确认了这一点，研究人员发现与特殊环境有关的学习焦虑会导致一些vBNST神经元活性的增加。

另外一篇文章中，Kim和同事希望了解背面BNST两个次区域（ovBNST和adBNST）中的细胞，是否差异调节焦虑。结果他们发现ovBNST神经元活性能促进焦虑，而且杏仁核——与恐惧，奖励和焦虑有关的大脑区域——信息则会激活adBNST神经元，减少焦虑，如果抑制这些信息就会增加焦虑。因此adBNST具有等同于减少焦虑的作用，这样说来两者具有不同的作用（见下图）。

（焦虑环路复合作用）

这两项研究令我们更深刻的了解了，焦虑如何通过BNST中对立又互补的神经回路表现出来的，研究指出了焦虑回路的模块特性，并提出一种双向调节焦虑相关应答的协调机制。这种双向调节作用在其它焦虑环路中也可以看到，尤其是对于大脑内侧前额叶皮质——单个神经元能差异表现安全和焦虑产生环境。

事实上，这种类型的神经环路设计可能就是恐惧和焦虑系统的一般特征。一些明确的证据表明不同的神经元亚群参与了恐惧和恐惧学习来源的安全感（safety-from-fear learning）。此外，恐惧和焦虑从概念上来说，密切相关，像是杏仁核，内侧前额叶皮质，海马和BNST之类的大脑区域也都同时涉及到这两方面。了解这两个系统共同的规律，以及它们各自的神经环路如何相互作用的，将是未来研究的重点方向。

（生物通：张迪）

原文摘要：

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

The co-morbidity of anxiety and dysfunctional reward processing in illnesses such as addiction1 and depression2 suggests that common neural circuitry contributes to these disparate neuropsychiatric symptoms. The extended amygdala, including the bed nucleus of the stria terminalis (BNST), modulates fear and anxiety3, 4, but also projects to the ventral tegmental area (VTA)5, 6, a region implicated in reward and aversion7, 8, 9, 10, 11, 12, 13, thus providing a candidate neural substrate for integrating diverse emotional states. However, the precise functional connectivity between distinct BNST projection neurons and their postsynaptic targets in the VTA, as well as the role of this circuit in controlling motivational states, have not been described. Here we record and manipulate the activity of genetically and neurochemically identified VTA-projecting BNST neurons in freely behaving mice. Collectively, aversive stimuli exposure produced heterogeneous firing patterns in VTA-projecting BNST neurons. By contrast, in vivo optically identified glutamatergic projection neurons displayed a net enhancement of activity to aversive stimuli, whereas the firing rate of identified GABAergic (γ-aminobutyric acid-containing) projection neurons was suppressed. Channelrhodopsin-2-assisted circuit mapping revealed that both BNST glutamatergic and GABAergic projections preferentially innervate postsynaptic non-dopaminergic VTA neurons, thus providing a mechanistic framework for in vivo circuit perturbations. In vivo photostimulation of BNST glutamatergic projections resulted in aversive and anxiogenic behavioural phenotypes. Conversely, activation of BNST GABAergic projections produced rewarding and anxiolytic phenotypes, which were also recapitulated by direct inhibition of VTA GABAergic neurons. These data demonstrate that functionally opposing BNST to VTA circuits regulate rewarding and aversive motivational states, and may serve as a crucial circuit node for bidirectionally normalizing maladaptive behaviours.

 

Distinct extended amygdala circuits for divergent motivational states

The co-morbidity of anxiety and dysfunctional reward processing in illnesses such as addiction1 and depression2 suggests that common neural circuitry contributes to these disparate neuropsychiatric symptoms. The extended amygdala, including the bed nucleus of the stria terminalis (BNST), modulates fear and anxiety3, 4, but also projects to the ventral tegmental area (VTA)5, 6, a region implicated in reward and aversion7, 8, 9, 10, 11, 12, 13, thus providing a candidate neural substrate for integrating diverse emotional states. However, the precise functional connectivity between distinct BNST projection neurons and their postsynaptic targets in the VTA, as well as the role of this circuit in controlling motivational states, have not been described. Here we record and manipulate the activity of genetically and neurochemically identified VTA-projecting BNST neurons in freely behaving mice. Collectively, aversive stimuli exposure produced heterogeneous firing patterns in VTA-projecting BNST neurons. By contrast, in vivo optically identified glutamatergic projection neurons displayed a net enhancement of activity to aversive stimuli, whereas the firing rate of identified GABAergic (γ-aminobutyric acid-containing) projection neurons was suppressed. Channelrhodopsin-2-assisted circuit mapping revealed that both BNST glutamatergic and GABAergic projections preferentially innervate postsynaptic non-dopaminergic VTA neurons, thus providing a mechanistic framework for in vivo circuit perturbations. In vivo photostimulation of BNST glutamatergic projections resulted in aversive and anxiogenic behavioural phenotypes. Conversely, activation of BNST GABAergic projections produced rewarding and anxiolytic phenotypes, which were also recapitulated by direct inhibition of VTA GABAergic neurons. These data demonstrate that functionally opposing BNST to VTA circuits regulate rewarding and aversive motivational states, and may serve as a crucial circuit node for bidirectionally normalizing maladaptive behaviours.