Letter | Published:

Distinct extended amygdala circuits for divergent motivational states

Nature volume 496, pages 224228 (11 April 2013) | Download Citation



The co-morbidity of anxiety and dysfunctional reward processing in illnesses such as addiction1 and depression2 suggests that common neural circuitry contributes to these disparate neuropsychiatric symptoms. The extended amygdala, including the bed nucleus of the stria terminalis (BNST), modulates fear and anxiety3,4, but also projects to the ventral tegmental area (VTA)5,6, a region implicated in reward and aversion7,8,9,10,11,12,13, thus providing a candidate neural substrate for integrating diverse emotional states. However, the precise functional connectivity between distinct BNST projection neurons and their postsynaptic targets in the VTA, as well as the role of this circuit in controlling motivational states, have not been described. Here we record and manipulate the activity of genetically and neurochemically identified VTA-projecting BNST neurons in freely behaving mice. Collectively, aversive stimuli exposure produced heterogeneous firing patterns in VTA-projecting BNST neurons. By contrast, in vivo optically identified glutamatergic projection neurons displayed a net enhancement of activity to aversive stimuli, whereas the firing rate of identified GABAergic (γ-aminobutyric acid-containing) projection neurons was suppressed. Channelrhodopsin-2-assisted circuit mapping revealed that both BNST glutamatergic and GABAergic projections preferentially innervate postsynaptic non-dopaminergic VTA neurons, thus providing a mechanistic framework for in vivo circuit perturbations. In vivo photostimulation of BNST glutamatergic projections resulted in aversive and anxiogenic behavioural phenotypes. Conversely, activation of BNST GABAergic projections produced rewarding and anxiolytic phenotypes, which were also recapitulated by direct inhibition of VTA GABAergic neurons. These data demonstrate that functionally opposing BNST to VTA circuits regulate rewarding and aversive motivational states, and may serve as a crucial circuit node for bidirectionally normalizing maladaptive behaviours.

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We thank M. Patel, J. Phillips and S. Maciver for assistance; V. Gukassyan and the UNC Neuroscience Center Microscopy Core (P30 NS045892), and members of the Stuber laboratory for discussion. We thank K. Deisseroth for viral constructs and the UNC Vector Core Facility for viral packaging. We thank B. Lowell and L. Vong for providing the Vgat-ires-cre and Vglut2-ires-cre mice. This study was supported by The Whitehall Foundation, The Foundation of Hope, National Institutes of Health grants DA029325 and DA032750 (to G.D.S.), AA018610 and AA007573 (to D.R.S.), NS007431 and DA034472 (to A.M.S.) and AA021043 (to K.P.), and the UNC NIAAA alcohol research center (AA011605).

Author information

Author notes

    • Joshua H. Jennings
    •  & Dennis R. Sparta

    These authors contributed equally to this work.


  1. Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA

    • Joshua H. Jennings
    • , Dennis R. Sparta
    • , Alice M. Stamatakis
    • , Randall L. Ung
    •  & Garret D. Stuber
  2. Neurobiology Curriculum, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA

    • Joshua H. Jennings
    • , Alice M. Stamatakis
    • , Thomas L. Kash
    •  & Garret D. Stuber
  3. Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA

    • Dennis R. Sparta
    • , Kristen E. Pleil
    • , Thomas L. Kash
    •  & Garret D. Stuber
  4. Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA

    • Kristen E. Pleil
    •  & Thomas L. Kash
  5. Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA

    • Thomas L. Kash
    •  & Garret D. Stuber
  6. Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA

    • Garret D. Stuber


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D.R.S., J.H.J. and G.D.S. designed all experiments and wrote the manuscript. All authors collected, analysed and discussed the data.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Garret D. Stuber.

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