Department of Pharmacology, University of Washington, Seattle, Washington, USA.
Nat Neurosci. 2011 May;14(5):620-6. doi: 10.1038/nn.2808. Epub 2011 Apr 17.
Generalized anxiety is thought to result, in part, from impairments in contingency awareness during conditioning to cues that predict aversive or fearful outcomes. Dopamine neurons of the ventral midbrain exhibit heterogeneous responses to aversive stimuli that are thought to provide a critical modulatory signal to facilitate orientation to environmental changes and assignment of motivational value to unexpected events. Here we describe a mouse model in which activation of dopamine neurons in response to an aversive stimulus is attenuated by conditional genetic inactivation of functional NMDA receptors on dopamine neurons. We discovered that altering the magnitude of excitatory responses by dopamine neurons in response to an aversive stimulus was associated with impaired conditioning to a cue that predicts an aversive outcome. Impaired conditioning by these mice was associated with the development of a persistent, generalized anxiety-like phenotype. These data are consistent with a role for dopamine in facilitating contingency awareness that is critical for the prevention of generalized anxiety.
广泛性焦虑被认为部分是由于在条件作用过程中对预测厌恶或恐惧结果的线索的关联性意识受损所致。中脑腹侧的多巴胺神经元对厌恶刺激表现出异质反应，这些反应被认为提供了关键的调节信号，以促进对环境变化的定向和对意外事件的动机价值的分配。在这里，我们描述了一种小鼠模型，其中通过条件性遗传失活多巴胺神经元上功能性 NMDA 受体，可减弱多巴胺神经元对厌恶刺激的反应。我们发现，改变多巴胺神经元对厌恶刺激的兴奋性反应幅度与对预测厌恶结果的线索的条件作用受损有关。这些小鼠的条件作用受损与持续的、广泛性焦虑样表型的发展有关。这些数据与多巴胺在促进对预防广泛性焦虑至关重要的关联性意识中的作用一致。
