Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Serotonin receptor 2c-expressing cells in the ventral CA1 control attention via innervation of the Edinger–Westphal nucleus

Abstract

The hippocampus is divided into dorsal and ventral zones along its principal axis. The dorsal hippocampus is critical for learning and memory, yet the basic function of the ventral hippocampus remains elusive. Here we genetically manipulate a subset of excitatory neurons expressing the serotonin receptor 2c (Htr2c) in the ventral hippocampus. Genetically modified virus tracing reveals that these Htr2c cells establish monosynaptic excitatory connections with newly identified neurons in the Edinger–Westphal nucleus (EW), which directly innervate the medial prefrontal cortex. Inactivation of Htr2c cells impairs behavioral performance in a visual-detection task that demands attention, without affecting novel-object recognition, learning, or memory. This attention deficit was recapitulated by inhibition of EW cells and rescued by activation of EW cells or synaptic projections from Htr2c cells onto EW cells. This study uncovers a synaptic pathway for control of attention.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Htr2c cells are a novel group of excitatory neurons.
Fig. 2: Htr2c cells directly innervate EW cells.
Fig. 3: Functional synaptic connections between Htr2c and EW cells.
Fig. 4: Inhibition of Htr2c cells impairs attention.
Fig. 5: Htr2c cells are activated in attention.
Fig. 6: Inhibition of EW cells impairs attention.
Fig. 7: Activation of EW cells enhances attention.

References

  1. 1.

    Kjelstrup, K. B. et al. Finite scale of spatial representation in the hippocampus. Science 321, 140–143 (2008).

    CAS  Article  Google Scholar 

  2. 2.

    Langston, R. F. et al. Development of the spatial representation system in the rat. Science 328, 1576–1580 (2010).

    CAS  Article  Google Scholar 

  3. 3.

    Miller, J. F. et al. Neural activity in human hippocampal formation reveals the spatial context of retrieved memories. Science 342, 1111–1114 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Gonçalves, J. T., Schafer, S. T. & Gage, F. H. Adult neurogenesis in the hippocampus: from stem cells to behavior. Cell 167, 897–914 (2016).

    Article  CAS  Google Scholar 

  5. 5.

    Voss, J. L., Bridge, D. J., Cohen, N. J. & Walker, J. A. A closer look at the hippocampus and memory. Trends Cogn. Sci. 21, 577–588 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Risold, P. Y. & Swanson, L. W. Structural evidence for functional domains in the rat hippocampus. Science 272, 1484–1486 (1996).

    CAS  Article  Google Scholar 

  7. 7.

    Fanselow, M. S. & Dong, H. W. Are the dorsal and ventral hippocampus functionally distinct structures? Neuron 65, 7–19 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Luo, L., Callaway, E. M. & Svoboda, K. Genetic dissection of neural circuits. Neuron 57, 634–660 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Dong, H. W., Swanson, L. W., Chen, L., Fanselow, M. S. & Toga, A. W. Genomic-anatomic evidence for distinct functional domains in hippocampal field CA1. Proc. Natl. Acad. Sci. USA 106, 11794–11799 (2009).

    CAS  Article  Google Scholar 

  10. 10.

    Thompson, C. L. et al. Genomic anatomy of the hippocampus. Neuron 60, 1010–1021 (2008).

    CAS  Article  Google Scholar 

  11. 11.

    Okuyama, T., Kitamura, T., Roy, D. S., Itohara, S. & Tonegawa, S. Ventral CA1 neurons store social memory. Science 353, 1536–1541 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Kitamura, T. et al. Island cells control temporal association memory. Science 343, 896–901 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Suh, J., Rivest, A. J., Nakashiba, T., Tominaga, T. & Tonegawa, S. Entorhinal cortex layer III input to the hippocampus is crucial for temporal association memory. Science 334, 1415–1420 (2011).

    CAS  Article  Google Scholar 

  14. 14.

    Schwab, M. H. et al. Neuronal basic helix-loop-helix proteins (NEX, neuroD, NDRF): spatiotemporal expression and targeted disruption of the NEX gene in transgenic mice. J. Neurosci. 18, 1408–1418 (1998).

    CAS  Article  Google Scholar 

  15. 15.

    Agarwal, A. et al. In vivo imaging and noninvasive ablation of pyramidal neurons in adult NEX-CreERT2 mice. Cereb. Cortex 22, 1473–1486 (2012).

    Article  Google Scholar 

  16. 16.

    Yang, X. et al. A novel mechanism of memory loss in Alzheimer’s disease mice via the degeneration of entorhinal-CA1 synapses. Mol. Psychiatry 23, 199–210 (2018).

    CAS  Article  Google Scholar 

  17. 17.

    Zhu, H. et al. Impairments of spatial memory in an Alzheimer’s disease model via degeneration of hippocampal cholinergic synapses. Nat. Commun. 8, 1676 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    McGovern, A. E. et al. Distinct brainstem and forebrain circuits receiving tracheal sensory neuron inputs revealed using a novel conditional anterograde transsynaptic viral tracing system. J. Neurosci. 35, 7041–7055 (2015).

    CAS  Article  Google Scholar 

  19. 19.

    Sun, N., Cassell, M. D. & Perlman, S. Anterograde, transneuronal transport of herpes simplex virus type 1 strain H129 in the murine visual system. J. Virol. 70, 5405–5413 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Erichsen, J. T., Wright, N. F. & May, P. J. Morphology and ultrastructure of medial rectus subgroup motoneurons in the macaque monkey. J. Comp. Neurol. 522, 626–641 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Horn, A. K. et al. Perioculomotor cell groups in monkey and man defined by their histochemical and functional properties: reappraisal of the Edinger-Westphal nucleus. J. Comp. Neurol. 507, 1317–1335 (2008).

    Article  Google Scholar 

  22. 22.

    O’Craven, K. M., Downing, P. E. & Kanwisher, N. fMRI evidence for objects as the units of attentional selection. Nature 401, 584–587 (1999).

    Article  Google Scholar 

  23. 23.

    Summerfield, J. J., Lepsien, J., Gitelman, D. R., Mesulam, M. M. & Nobre, A. C. Orienting attention based on long-term memory experience. Neuron 49, 905–916 (2006).

    CAS  Article  Google Scholar 

  24. 24.

    Cabeza, R., Ciaramelli, E., Olson, I. R. & Moscovitch, M. The parietal cortex and episodic memory: an attentional account. Nat. Rev. Neurosci. 9, 613–625 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Muzzio, I. A. et al. Attention enhances the retrieval and stability of visuospatial and olfactory representations in the dorsal hippocampus. PLoS Biol. 7, e1000140 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Liu, Z. X., Shen, K., Olsen, R. K. & Ryan, J. D. Visual sampling predicts hippocampal activity. J. Neurosci. 37, 599–609 (2017).

    CAS  Article  Google Scholar 

  27. 27.

    Mar, A. C. et al. The touchscreen operant platform for assessing executive function in rats and mice. Nat. Protoc. 8, 1985–2005 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Kim, H., Ährlund-Richter, S., Wang, X., Deisseroth, K. & Carlén, M. Prefrontal parvalbumin neurons in control of attention. Cell 164, 208–218 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Wimmer, R. D. et al. Thalamic control of sensory selection in divided attention. Nature 526, 705–709 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Baluch, F. & Itti, L. Mechanisms of top-down attention. Trends Neurosci. 34, 210–224 (2011).

    CAS  Article  Google Scholar 

  31. 31.

    Fosque, B. F. et al. Neural circuits. Labeling of active neural circuits in vivo with designed calcium integrators. Science 347, 755–760 (2015).

    CAS  Article  Google Scholar 

  32. 32.

    Zhang, S. et al. Selective attention. Long-range and local circuits for top-down modulation of visual cortex processing. Science 345, 660–665 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Gregoriou, G. G., Gotts, S. J., Zhou, H. & Desimone, R. High-frequency, long-range coupling between prefrontal and visual cortex during attention. Science 324, 1207–1210 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Miller, E. K. & Buschman, T. J. Cortical circuits for the control of attention. Curr. Opin. Neurobiol. 23, 216–222 (2013).

    CAS  Article  Google Scholar 

  35. 35.

    Carli, M., Evenden, J. L. & Robbins, T. W. Depletion of unilateral striatal dopamine impairs initiation of contralateral actions and not sensory attention. Nature 313, 679–682 (1985).

    CAS  Article  Google Scholar 

  36. 36.

    Humby, T., Laird, F. M., Davies, W. & Wilkinson, L. S. Visuospatial attentional functioning in mice: interactions between cholinergic manipulations and genotype. Eur. J. Neurosci. 11, 2813–2823 (1999).

    CAS  Article  Google Scholar 

  37. 37.

    Higgins, G. A. & Breysse, N. Rodent model of attention: the 5-choice serial reaction time task. Curr. Protocols Pharmacol. Chapter 5, 49 (2008).

    Google Scholar 

  38. 38.

    Amitai, N. & Markou, A. Disruption of performance in the five-choice serial reaction time task induced by administration of N-methyl-D-aspartate receptor antagonists: relevance to cognitive dysfunction in schizophrenia. Biol. Psychiatry 68, 5–16 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Semenova, S. & Markou, A. The effects of the mGluR5 antagonist MPEP and the mGluR2/3 antagonist LY341495 on rats’ performance in the 5-choice serial reaction time task. Neuropharmacology 52, 863–872 (2007).

    CAS  Article  Google Scholar 

  40. 40.

    Uchida, N. & Mainen, Z. F. Speed and accuracy of olfactory discrimination in the rat. Nat. Neurosci. 6, 1224–1229 (2003).

    CAS  Article  Google Scholar 

  41. 41.

    Jaramillo, S. & Zador, A. M. The auditory cortex mediates the perceptual effects of acoustic temporal expectation. Nat. Neurosci. 14, 246–251 (2011).

    CAS  Article  Google Scholar 

  42. 42.

    Ahrens, S. et al. ErbB4 regulation of a thalamic reticular nucleus circuit for sensory selection. Nat. Neurosci. 18, 104–111 (2015).

    CAS  Article  Google Scholar 

  43. 43.

    May, P. J., Reiner, A. J. & Ryabinin, A. E. Comparison of the distributions of urocortin-containing and cholinergic neurons in the perioculomotor midbrain of the cat and macaque. J. Comp. Neurol. 507, 1300–1316 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Horn, A. K., Schulze, C. & Radtke-Schuller, S. The Edinger-Westphal nucleus represents different functional cell groups in different species. Ann. NY Acad. Sci. 1164, 45–50 (2009).

    Article  Google Scholar 

  45. 45.

    Ryabinin, A. E., Criado, J. R., Henriksen, S. J., Bloom, F. E. & Wilson, M. C. Differential sensitivity of c-Fos expression in hippocampus and other brain regions to moderate and low doses of alcohol. Mol. Psychiatry 2, 32–43 (1997).

    CAS  Article  Google Scholar 

  46. 46.

    Kozicz, T. et al. The Edinger-Westphal nucleus: a historical, structural, and functional perspective on a dichotomous terminology. J. Comp. Neurol. 519, 1413–1434 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Morawski, M. et al. Distinct glutaminyl cyclase expression in Edinger-Westphal nucleus, locus coeruleus and nucleus basalis Meynert contributes to pGlu-Abeta pathology in Alzheimer’s disease. Acta Neuropathol. 120, 195–207 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Spencer, S. J. et al. Ghrelin regulates the hypothalamic-pituitary-adrenal axis and restricts anxiety after acute stress. Biol. Psychiatry 72, 457–465 (2012).

    CAS  Article  Google Scholar 

  49. 49.

    Tu, W. et al. DAPK1 interaction with NMDA receptor NR2B subunits mediates brain damage in stroke. Cell 140, 222–234 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Yang, Y. et al. EPAC null mutation impairs learning and social interactions via aberrant regulation of miR-124 and Zif268 translation. Neuron 73, 774–788 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Zeng, W. B. et al. Anterograde monosynaptic transneuronal tracers derived from herpes simplex virus 1 strain H129. Mol. Neurodegener. 12, 38 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Coulon, P. et al. Activity modes in thalamocortical relay neurons are modulated by G(q)/G(11) family G-proteins - serotonergic and glutamatergic signaling. Front. Cell. Neurosci. 4, 132 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Del Pino, I. et al. Abnormal wiring of CCK+ basket cells disrupts spatial information coding. Nat. Neurosci. 20, 784–792 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Giardino, W. J., Cote, D. M., Li, J. & Ryabinin, A. E. Characterization of genetic differences within the centrally projecting Edinger-Westphal nucleus of C57BL/6J and DBA/2J mice by expression profiling. Front. Neuroanat. 6, 5 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Bäckberg, M., Hervieu, G., Wilson, S. & Meister, B. Orexin receptor-1 (OX-R1) immunoreactivity in chemically identified neurons of the hypothalamus: focus on orexin targets involved in control of food and water intake. Eur. J. Neurosci. 15, 315–328 (2002).

    Article  Google Scholar 

  56. 56.

    Hitti, F. L. & Siegelbaum, S. A. The hippocampal CA2 region is essential for social memory. Nature 508, 88–92 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Feng, S. et al. Canonical transient receptor potential 3 channels regulate mitochondrial calcium uptake. Proc. Natl. Acad. Sci. USA 110, 11011–11016 (2013).

    CAS  Article  Google Scholar 

  58. 58.

    Sugiyama, T., Osumi, N. & Katsuyama, Y. A novel cell migratory zone in the developing hippocampal formation. J. Comp. Neurol. 522, 3520–3538 (2014).

    CAS  Article  Google Scholar 

  59. 59.

    Volta, M. et al. Initial elevations in glutamate and dopamine neurotransmission decline with age, as does exploratory behavior, in LRRK2 G2019S knock-in mice. eLife 6, e28377 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Willems, J. G. P., Wadman, W. J. & Cappaert, N. L. M. Parvalbumin interneuron mediated feedforward inhibition controls signal output in the deep layers of the perirhinal-entorhinal cortex. Hippocampus 28, 281–296 (2018).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank S. Duan at Zhejiang University, Hangzhou, China, for providing GAD1-Cre mice; M.-H. Luo at Wuhan Institute of Virology, Chinese Academy of Sciences, for the construction and generation of rAAV1/2-DIO-TK, rAAV1/2-DIO-TK-GFP, H129ΔTK-mCh, and H129ΔTK-GFP virus particles; and F. Xu at Britton Chance Center for Biomedical Photonics, Chinese Academy of Sciences, for the construction and generation of RV. This work was supported by the National Natural Science Foundation of China (Grants: 31721002 to YL; 91632306 to Y.L.; 51627807 to Y.L.; 81771150, 81761138043, and 91632114 to L.Q.Z.), the National Program for Support of Top-Notch Young Professionals, and Academic Frontier Youth Team of HUST (to L.Q.Z.).

Author information

Affiliations

Authors

Contributions

Y.L., L.Q.Z., and Q.T. conceived and designed the studies and wrote the paper. X.L., W.C., and K.P. carried out synaptic tracing, mutagenesis and virus construction, and behavioral and optogenetic studies. H.L., P.P., and Y.G. performed electrophysiological studies and immunohistochemistry. S.S., Y.C., L.P., H.K.A., and D.L. performed genotyping, PCR, and cell-counting. All authors contributed to the data analysis and presentation in the paper.

Corresponding authors

Correspondence to Ling-Qiang Zhu or Youming Lu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–22

Reporting Summary

Supplementary Table 1

5 stages of 5-CSRT task training schedules

Supplementary Video 1

Correct trial

Supplementary Video 2

Incorrect trial

Supplementary Video 3

Premature trial

Supplementary Video 4

Omission trial

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Li, X., Chen, W., Pan, K. et al. Serotonin receptor 2c-expressing cells in the ventral CA1 control attention via innervation of the Edinger–Westphal nucleus. Nat Neurosci 21, 1239–1250 (2018). https://doi.org/10.1038/s41593-018-0207-0

Download citation

Further reading

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