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

Abstract

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.

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Figure 1: NMDARs control amplitude of activation of dopamine neurons in response to tail pinch.
Figure 2: Cue-dependent fear conditioning is impaired in knockout mice.
Figure 3: Sensitization of ASR following fear conditioning in knockout mice is context independent.
Figure 4: Anxiety-related behavior is enhanced in knockout mice following foot shock conditioning.
Figure 5: Sensory motor gating, peripheral stress response and monoamine levels are not altered following foot shock conditioning.
Figure 6: Conditional restoration of NMDAR signaling to ventral midbrain dopamine neurons prevents generalized anxiety-like behavior.

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Acknowledgements

We thank A.D. Guler and members of the Palmiter laboratory for thoughtful discussion of this manuscript. We thank G. Froelich, V. Wall and M.J. Kim for technical support. This work was supported in part by US National Institutes of Health grants 2T32 GM007270 (to J.P.F.), 4 R25 GM 058501-05 (to T.M.K.D.) and 1 R01 MH58755 (to S.J.Y.M.).

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Contributions

L.S.Z. and J.P.F. designed the experiments. L.S.Z. performed in vivo recordings with assistance from G.L.J. and S.J.Y.M. L.S.Z. and J.P.F. performed behavioral experiments with assistance from M.G.G. and T.M.K.D. E.A. performed slice physiology with support from A.B. R.D.P. constructed the AAV1-fs-HA-NR1 viral vector. J.M.A. purified AAV1-fs-HA-NR1. The manuscript was written by L.S.Z. with assistance from J.P.F. and R.D.P.

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Correspondence to Larry S Zweifel or Richard D Palmiter.

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Zweifel, L., Fadok, J., Argilli, E. et al. Activation of dopamine neurons is critical for aversive conditioning and prevention of generalized anxiety. Nat Neurosci 14, 620–626 (2011). https://doi.org/10.1038/nn.2808

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