Distinct extended amygdala circuits for divergent motivational states



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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Figure 1: Optogenetic identification of vBNST–VTA projection neurons.
Figure 2: Excitatory and inhibitory synapses onto non-dopaminergic VTA neurons from neurochemically distinct vBNST neurons.
Figure 3: Vglut2vBNST–VTA and VgatvBNST–VTA projection neurons display distinct firing patterns in response to foot-shock and shock-associated contextual cues.
Figure 4: Photostimulation of the Vglut2vBNST–VTA pathway promotes aversion and anxiety.
Figure 5: Photostimulation of the VgatvBNST–VTA pathway and inhibition of VgatVTA neurons produces reward-related behaviours and attenuates anxiety.


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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).

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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.

Corresponding author

Correspondence to Garret D. Stuber.

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The authors declare no competing financial interests.

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Jennings, J., Sparta, D., Stamatakis, A. et al. Distinct extended amygdala circuits for divergent motivational states. Nature 496, 224–228 (2013). https://doi.org/10.1038/nature12041

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