Coding the direct/indirect pathways by D1 and D2 receptors is not valid for accumbens projections (original) (raw)

Nature Neuroscience volume 18, pages 1230–1232 (2015)Cite this article

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Abstract

It is widely accepted that D1 dopamine receptor–expressing striatal neurons convey their information directly to the output nuclei of the basal ganglia, whereas D2-expressing neurons do so indirectly via pallidal neurons. Combining optogenetics and electrophysiology, we found that this architecture does not apply to mouse nucleus accumbens projections to the ventral pallidum. Thus, current thinking attributing D1 and D2 selectivity to accumbens projections akin to dorsal striatal pathways needs to be reconsidered.

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References

  1. Bock, R. et al. Nat. Neurosci. 16, 632–638 (2013).
    Article CAS Google Scholar
  2. MacAskill, A.F., Cassel, J.M. & Carter, A.G. Nat. Neurosci. 17, 1198–1207 (2014).
    Article CAS Google Scholar
  3. Yawata, S., Yamaguchi, T., Danjo, T., Hikida, T. & Nakanishi, S. Proc. Natl. Acad. Sci. USA 109, 12764–12769 (2012).
    Article CAS Google Scholar
  4. Gerfen, C.R. & Surmeier, D.J. Annu. Rev. Neurosci. 34, 441–466 (2011).
    Article CAS Google Scholar
  5. Cazorla, M. et al. Neuron 81, 153–164 (2014).
    Article CAS Google Scholar
  6. Saunders, A. et al. Nature 521, 85–89 (2015).
    Article CAS Google Scholar
  7. MacAskill, A.F., Little, J.P., Cassel, J.M. & Carter, A.G. Nat. Neurosci. 15, 1624–1626 (2012).
    Article CAS Google Scholar
  8. Smith, R.J., Lobo, M.K., Spencer, S. & Kalivas, P.W. Curr. Opin. Neurobiol. 23, 546–552 (2013).
    Article CAS Google Scholar
  9. Tripathi, A., Prensa, L. & Mengual, E. Brain Struct. Funct. 218, 1133–1157 (2013).
    Article Google Scholar
  10. Zahm, D.S., Zaborszky, L., Alheid, G.F. & Heimer, L. J. Comp. Neurol. 255, 592–605 (1987).
    Article CAS Google Scholar
  11. Lu, X.-Y., Ghasemzadeh, M.B. & Kalivas, P.W. Neuroscience 82, 767–780 (1998).
    Article CAS Google Scholar
  12. Bocklisch, C. et al. Science 341, 1521–1525 (2013).
    Article CAS Google Scholar
  13. Watabe-Uchida, M., Zhu, L., Ogawa, S.K., Vamanrao, A. & Uchida, N. Neuron 74, 858–873 (2012).
    Article CAS Google Scholar
  14. Leung, B.K. & Balleine, B.W. J. Neurosci. 35, 4953–4964 (2015).
    Article CAS Google Scholar
  15. Bertran-Gonzalez, J. et al. J. Neurosci. 28, 5671–5685 (2008).
    Article CAS Google Scholar
  16. Thibault, D., Loustalot, F., Fortin, G.M., Bourque, M.J. & Trudeau, L.E. PLoS ONE 8, e67219 (2013).
    Article CAS Google Scholar
  17. Kravitz, A.V., Tye, L.D. & Kreitzer, A.C. Nat. Neurosci. 15, 816–818 (2012).
    Article CAS Google Scholar
  18. Lobo, M.K. & Nestler, E.J. Front. Neuroanat. 5, 41 (2011).
    Article Google Scholar
  19. Mogenson, G.J., Jones, D.J. & Yim, C.Y. Prog. Neurobiol. 14, 69–97 (1980).
    Article CAS Google Scholar
  20. Stefanik, M.T., Kupchik, Y.M., Brown, R.M. & Kalivas, P.W. J. Neurosci. 33, 13654–13662 (2013).
    Article CAS Google Scholar
  21. Gong, S. et al. J. Neurosci. 27, 9817–9823 (2007).
    Article CAS Google Scholar
  22. Gong, S. et al. Nature 425, 917–925 (2003).
    Article CAS Google Scholar
  23. Bengtson, C.P. & Osborne, P.B. J. Neurophysiol. 83, 2649–2660 (2000).
    Article CAS Google Scholar
  24. Kupchik, Y.M. & Kalivas, P.W. Brain Struct. Funct. 218, 1487–1500 (2013).
    Article Google Scholar

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Acknowledgements

We thank T.C. Jhou and R.J. Smith for their assistance with the histology experiments. We thank E.J. Nestler (Mount Sinai School of Medicine) for providing D1-Cre and D2-Cre breeding pairs, and R. Gregory and J. Hyang for genotyping the mice. This work was supported by US Public Health Service grants DA03906, DA12513 and DA015369, and a fellowship from the Neuroscience Institute, Medical University of South Carolina.

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Authors and Affiliations

  1. Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina, USA
    Yonatan M Kupchik, Robyn M Brown, Jasper A Heinsbroek, Danielle J Schwartz & Peter W Kalivas
  2. Department of Medical Neurobiology, Institute for Medical Research Israel-Canada, The Hebrew University, Jerusalem, Israel
    Yonatan M Kupchik
  3. Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Australia
    Robyn M Brown
  4. Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland, USA
    Mary Kay Lobo

Authors

  1. Yonatan M Kupchik
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  2. Robyn M Brown
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  3. Jasper A Heinsbroek
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  4. Mary Kay Lobo
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  5. Danielle J Schwartz
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  6. Peter W Kalivas
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Contributions

Y.M.K. and P.W.K. designed the experiments. Y.M.K., R.M.B. and D.J.S. performed microinjection surgeries. J.A.H. and M.K.L. performed double-labeling studies. Y.M.K. performed electrophysiology and histology experiments, and analyzed the data. Y.M.K. and P.W.K. wrote the paper. All of the authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence toYonatan M Kupchik or Peter W Kalivas.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Location of virus injection into the accumbens and GFP-expressing fibers in the dVP.

(a) Drawing of the spread of GFP in the nucleus accumbens in 7 representative virus injections. Note that while most injections were localized entirely in the ventral NAcore, some injections partly invaded the adjacent shell subcompartment. (b) Montage showing GFP fibers within the dVP. Recordings were made only at the site of GFP fluorescence. AC- anterior commissure. Bar=1 mm. (c) Magnification of the boxed area in panel b. Bar= 100 µm.

Supplementary Figure 2 Cre-ChR2 does not induce non-specific IPSCs.

(a) Schematic of experiment. Cre-dependent ChR2 was injected into the nucleus accumbens of wild-type mice and neurons were patched in the VP 2 weeks after injections. Pulses of blue LED light were applied similar to the protocol used in Figure 1 in the main text to induce ChR-driven IPSCs. (b) Representative recordings from a VP neuron showing that LED pulses (red horizontal lines) did not generate IPSCs when Cre-ChR2 was injected into the accumbens of a WT mouse. This was replicated in 5 more neurons.

Supplementary Figure 3 NAc D1-MSN terminals to the VM innervate selectively neurons with GABA-like properties.

(a) Out of 15 neurons (n = 3 mice) tested in the VM 10 neurons exhibited eIPSCs generated by D1-MSN terminals while 5 neurons did not respond. Cell numbers in each group correspond also to the appropriate groups in b-e. (b) The D1-MSN-responding VM neurons did not exhibit significant I_h_ (-24.1±6.8 pA) while the non-responding VM neurons showed robust I_h_ (-178.3±35.0 pA, unpaired t-test, t(13)=5.74, p<0.0001). I_h_ was calculated as the difference between the currents during the first and the last 100 ms of the 2 s long hyperpolarizing step. Bottom – representative I_h_ recordings for D1-responding (left) and D1 non-responding (right) VM neurons. (c) VM neurons receiving D1-MSN input from the NAc showed higher action potential firing rate compared to VM neurons not receiving D1-MSN input (7.97±1.3 Hz vs. 0.02±0.02 Hz, respectively; unpaired t-test, t(13)=5.05, p=0.0005). (d) VM neurons receiving D1-MSN input from the NAc showed higher sIPSC frequency compared to VM neurons not receiving D1-MSN input (6.65±0.74 Hz and 1.83±0.75 Hz, respectively; unpaired t-test, t(13)=4.20, p=0.0012). (e) VM neurons receiving D1-MSN input from the NAc showed higher sIPSC amplitude compared to VM neurons not receiving D1-MSN input (72.3±7.4 pA and 35.1±2.8 pA, respectively; unpaired t-test, t(13)=3.61, p=0.0036). Results are presented as mean±s.e.m. Error bars represent s.e.m. *, p<0.05.

Supplementary Figure 4 D1-MSN input to the GP is weaker than that of the VP.

(a) Representative image of injection sites of Cre-dependent ChR2 into the dorsal striatum (D2-Cre mouse). Calibration bar – 500 μm. (b) In the GP almost all cells received dorsal striatum D2-MSN input while only 18% received D1-MSN input. (c) Representative eIPSCs recorded in a GP (a) or a VP (b) neuron and generated by 10 consecutive stimulations of D1-MSN input from the dorsal striatum or the NAc, respectively. Red trace represents the average of traces. (d) Failure rate (% trials showing failures) in GP neurons receiving D1-MSN input (6.0±6.0%) was similar to that in the VP (5.1±2.7%). (e) The amplitude of eIPSCs generated by D1-MSN input to the GP (85±48 pA) was lower than that measured in the VP (359±79 pA). (f) The latency for the eIPSC in the GP and the VP was the same (1.57±0.32 ms and 1.72±0.14 ms, respectively). Results are presented as mean±s.e.m. Error bars represent s.e.m.

Supplementary Figure 5 Representative sections quantified for number of D1-, D2- and D1+D2-expressing MSNs in BAC transgenic mice expressing different reporter proteins in D1 and D2 MSNs.

The top 3 panels show labeling for D1-tomato (red) and D2-GFP (green) MSNs, and D1+D2 MSNs are indicated by yellow (also indicated by white arrowheads). Actual counts are shown in Supplementary Table 3. Micrographs were specifically chosen to contain a relatively high number of D1+D2 MSNs. Bottom panels show the same sections counter-stained for Neun (blue) and it can be seen that the vast majority of neurons are either D1 or D2 MSNs. Bar=50 µm.

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Kupchik, Y., Brown, R., Heinsbroek, J. et al. Coding the direct/indirect pathways by D1 and D2 receptors is not valid for accumbens projections.Nat Neurosci 18, 1230–1232 (2015). https://doi.org/10.1038/nn.4068

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