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

Nature Neuroscience volume 14, pages 620626 (2011) | Download Citation


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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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.).

Author information

Author notes

    • Larry S Zweifel
    •  & Jonathan P Fadok

    These authors contributed equally to this work.


  1. Department of Pharmacology, University of Washington, Seattle, Washington, USA.

    • Larry S Zweifel
    •  & Graham L Jones
  2. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA.

    • Larry S Zweifel
    •  & Graham L Jones
  3. Department of Biochemistry and Howard Hughes Medical Institute, University of Washington, Seattle, Washington, USA.

    • Larry S Zweifel
    • , Jonathan P Fadok
    • , Tavis M K Dickerson
    •  & Richard D Palmiter
  4. Graduate Program in Neurobiology and Behavior, University of Washington, Seattle, Washington, USA.

    • Jonathan P Fadok
    •  & Michael G Garelick
  5. Ernest Gallo Clinic and Research Center and Department of Neurology, University of California, San Francisco, San Francisco, California, USA.

    • Emmanuela Argilli
    •  & Antonello Bonci
  6. Department of Neurology, University of Washington, Seattle, Washington, USA.

    • James M Allen
  7. Department of Psychology, University of Washington, Seattle, Washington, USA.

    • Sheri J Y Mizumori


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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.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Larry S Zweifel or Richard D Palmiter.

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