Activation of dopamine neurons is critical for aversive conditioning and prevention of generalized anxiety

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Abstract
Midbrain dopaminergic neuron activity is associated with reward signaling and aversive stimuli. Using genetic models in which excitatory response of dopaminergic neurons are reduced, the authors find that the imbalance of dopaminergic neuronal response following aversive stimuli is manifested in 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 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.