Activation of Dopamine Neurons is Critical for Aversive Conditioning and Prevention of Generalized Anxiety

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 orienting 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 N–methyl–D–aspartate–type glutamate receptors (NMDARs) on dopamine neurons. We discovered that altering the magnitude of excitatory responses by dopamine neurons in response to an aversive stimulus is associated with impaired conditioning to a cue that predicts an aversive outcome. Impaired conditioning by these mice is associated with 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.