Distinct extended amygdala circuits for divergent motivational states

Subjects

Abstract

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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.

References

  1. 1

    Koob, G. F. & Le Moal, M. Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology 24, 97–129 (2001)

    CAS  Article  Google Scholar 

  2. 2

    Nestler, E. J. & Carlezon, W. A., Jr The mesolimbic dopamine reward circuit in depression. Biol. Psychiatry 59, 1151–1159 (2006)

    CAS  Article  Google Scholar 

  3. 3

    Davis, M., Walker, D. L., Miles, L. & Grillon, C. Phasic vs sustained fear in rats and humans: role of the extended amygdala in fear vs anxiety. Neuropsychopharmacology 35, 105–135 (2010)

    Article  Google Scholar 

  4. 4

    Walker, D. L. & Davis, M. Role of the extended amygdala in short-duration versus sustained fear: a tribute to Dr. Lennart Heimer. Brain Struct. Funct. 213, 29–42 (2008)

    Article  Google Scholar 

  5. 5

    Geisler, S. & Zahm, D. S. Afferents of the ventral tegmental area in the rat-anatomical substratum for integrative functions. J. Comp. Neurol. 490, 270–294 (2005)

    Article  Google Scholar 

  6. 6

    Georges, F. & Aston-Jones, G. Potent regulation of midbrain dopamine neurons by the bed nucleus of the stria terminalis. J. Neurosci. 21, RC160 (2001)

    CAS  Article  Google Scholar 

  7. 7

    Cohen, J. Y., Haesler, S., Vong, L., Lowell, B. B. & Uchida, N. Neuron-type-specific signals for reward and punishment in the ventral tegmental area. Nature 482, 85–88 (2012)

    CAS  Article  ADS  Google Scholar 

  8. 8

    Fields, H. L., Hjelmstad, G. O., Margolis, E. B. & Nicola, S. M. Ventral tegmental area neurons in learned appetitive behavior and positive reinforcement. Annu. Rev. Neurosci. 30, 289–316 (2007)

    CAS  Article  Google Scholar 

  9. 9

    Lammel, S. et al. Input-specific control of reward and aversion in the ventral tegmental area. Nature 491, 212–217 (2012)

    CAS  Article  ADS  Google Scholar 

  10. 10

    Stamatakis, A. M. & Stuber, G. D. Activation of lateral habenula inputs to the ventral midbrain promotes behavioral avoidance. Nature Neurosci. 15, 1105–1107 (2012)

    CAS  Article  Google Scholar 

  11. 11

    Tan, K. R. et al. GABA neurons of the VTA drive conditioned place aversion. Neuron 73, 1173–1183 (2012)

    CAS  Article  Google Scholar 

  12. 12

    Tye, K. M. et al. Dopamine neurons modulate neural encoding and expression of depression-related behaviour. Nature 493, 537–541 (2012)

    Article  ADS  Google Scholar 

  13. 13

    van Zessen, R., Phillips, J. L., Budygin, E. A. & Stuber, G. D. Activation of VTA GABA neurons disrupts reward consumption. Neuron 73, 1184–1194 (2012)

    CAS  Article  Google Scholar 

  14. 14

    Hammack, S. E., Mania, I. & Rainnie, D. G. Differential expression of intrinsic membrane currents in defined cell types of the anterolateral bed nucleus of the stria terminalis. J. Neurophysiol. 98, 638–656 (2007)

    CAS  Article  Google Scholar 

  15. 15

    Dong, H. W. & Swanson, L. W. Organization of axonal projections from the anterolateral area of the bed nuclei of the stria terminalis. J. Comp. Neurol. 468, 277–298 (2004)

    Article  Google Scholar 

  16. 16

    Dumont, E. C. & Williams, J. T. Noradrenaline triggers GABAA inhibition of bed nucleus of the stria terminalis neurons projecting to the ventral tegmental area. J. Neurosci. 24, 8198–8204 (2004)

    CAS  Article  Google Scholar 

  17. 17

    Jalabert, M., Aston-Jones, G., Herzog, E., Manzoni, O. & Georges, F. Role of the bed nucleus of the stria terminalis in the control of ventral tegmental area dopamine neurons. Prog. Neuropsychopharmacol. Biol. Psychiatry 33, 1336–1346 (2009)

    CAS  Article  Google Scholar 

  18. 18

    Kudo, T. et al. Three types of neurochemical projection from the bed nucleus of the stria terminalis to the ventral tegmental area in adult mice. J. Neurosci. 32, 18035–18046 (2012)

    CAS  Article  Google Scholar 

  19. 19

    Briand, L. A., Vassoler, F. M., Pierce, R. C., Valentino, R. J. & Blendy, J. A. Ventral tegmental afferents in stress-induced reinstatement: the role of cAMP response element-binding protein. J. Neurosci. 30, 16149–16159 (2010)

    CAS  Article  Google Scholar 

  20. 20

    Christianson, J. P. et al. Safety signals mitigate the consequences of uncontrollable stress via a circuit involving the sensory insular cortex and bed nucleus of the stria terminalis. Biol. Psychiatry 70, 458–464 (2011)

    Article  Google Scholar 

  21. 21

    Mahler, S. V. & Aston-Jones, G. S. Fos activation of selective afferents to ventral tegmental area during cue-induced reinstatement of cocaine seeking in rats. J. Neurosci. 32, 13309–13325 (2012)

    CAS  Article  Google Scholar 

  22. 22

    Boyden, E. S., Zhang, F., Bamberg, E., Nagel, G. & Deisseroth, K. Millisecond-timescale, genetically targeted optical control of neural activity. Nature Neurosci. 8, 1263–1268 (2005)

    CAS  Article  Google Scholar 

  23. 23

    Fuller, J. H. & Schlag, J. D. Determination of antidromic excitation by the collision test: problems of interpretation. Brain Res. 112, 283–298 (1976)

    CAS  Article  Google Scholar 

  24. 24

    Sparta, D. R. et al. Construction of implantable optical fibers for long-term optogenetic manipulation of neural circuits. Nature Protocols 7, 12–23 (2012)

    CAS  Article  Google Scholar 

  25. 25

    Nagy, F. Z. & Pare, D. Timing of impulses from the central amygdala and bed nucleus of the stria terminalis to the brain stem. J. Neurophysiol. 100, 3429–3436 (2008)

    Article  Google Scholar 

  26. 26

    Vong, L. et al. Leptin action on GABAergic neurons prevents obesity and reduces inhibitory tone to POMC neurons. Neuron 71, 142–154 (2011)

    CAS  Article  Google Scholar 

  27. 27

    Stuber, G. D. et al. Excitatory transmission from the amygdala to nucleus accumbens facilitates reward seeking. Nature 475, 377–380 (2011)

    CAS  Article  Google Scholar 

  28. 28

    Erb, S., Shaham, Y. & Stewart, J. Stress-induced relapse to drug seeking in the rat: role of the bed nucleus of the stria terminalis and amygdala. Stress 4, 289–303 (2001)

    CAS  Article  Google Scholar 

  29. 29

    Poulos, A. M., Ponnusamy, R., Dong, H. W. & Fanselow, M. S. Compensation in the neural circuitry of fear conditioning awakens learning circuits in the bed nuclei of the stria terminalis. Proc. Natl Acad. Sci. USA 107, 14881–14886 (2010)

    CAS  Article  ADS  Google Scholar 

  30. 30

    Phelps, E. A. & LeDoux, J. E. Contributions of the amygdala to emotion processing: from animal models to human behavior. Neuron 48, 175–187 (2005)

    CAS  Article  Google Scholar 

  31. 31

    Roitman, M. F., Wheeler, R. A. & Carelli, R. M. Nucleus accumbens neurons are innately tuned for rewarding and aversive taste stimuli, encode their predictors, and are linked to motor output. Neuron 45, 587–597 (2005)

    CAS  Article  Google Scholar 

  32. 32

    Tye, K. M. & Janak, P. H. Amygdala neurons differentially encode motivation and reinforcement. J. Neurosci. 27, 3937–3945 (2007)

    CAS  Article  Google Scholar 

Download references

Acknowledgements

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

Affiliations

Authors

Contributions

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.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-19 and Supplementary Table 1. (PDF 5876 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing