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.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Kjelstrup, K. B. et al. Finite scale of spatial representation in the hippocampus. Science 321, 140–143 (2008).
Langston, R. F. et al. Development of the spatial representation system in the rat. Science 328, 1576–1580 (2010).
Miller, J. F. et al. Neural activity in human hippocampal formation reveals the spatial context of retrieved memories. Science 342, 1111–1114 (2013).
Gonçalves, J. T., Schafer, S. T. & Gage, F. H. Adult neurogenesis in the hippocampus: from stem cells to behavior. Cell 167, 897–914 (2016).
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).
Risold, P. Y. & Swanson, L. W. Structural evidence for functional domains in the rat hippocampus. Science 272, 1484–1486 (1996).
Fanselow, M. S. & Dong, H. W. Are the dorsal and ventral hippocampus functionally distinct structures? Neuron 65, 7–19 (2010).
Luo, L., Callaway, E. M. & Svoboda, K. Genetic dissection of neural circuits. Neuron 57, 634–660 (2008).
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).
Thompson, C. L. et al. Genomic anatomy of the hippocampus. Neuron 60, 1010–1021 (2008).
Okuyama, T., Kitamura, T., Roy, D. S., Itohara, S. & Tonegawa, S. Ventral CA1 neurons store social memory. Science 353, 1536–1541 (2016).
Kitamura, T. et al. Island cells control temporal association memory. Science 343, 896–901 (2014).
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).
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).
Agarwal, A. et al. In vivo imaging and noninvasive ablation of pyramidal neurons in adult NEX-CreERT2 mice. Cereb. Cortex 22, 1473–1486 (2012).
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).
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).
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).
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).
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).
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).
O’Craven, K. M., Downing, P. E. & Kanwisher, N. fMRI evidence for objects as the units of attentional selection. Nature 401, 584–587 (1999).
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).
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).
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).
Liu, Z. X., Shen, K., Olsen, R. K. & Ryan, J. D. Visual sampling predicts hippocampal activity. J. Neurosci. 37, 599–609 (2017).
Mar, A. C. et al. The touchscreen operant platform for assessing executive function in rats and mice. Nat. Protoc. 8, 1985–2005 (2013).
Kim, H., Ährlund-Richter, S., Wang, X., Deisseroth, K. & Carlén, M. Prefrontal parvalbumin neurons in control of attention. Cell 164, 208–218 (2016).
Wimmer, R. D. et al. Thalamic control of sensory selection in divided attention. Nature 526, 705–709 (2015).
Baluch, F. & Itti, L. Mechanisms of top-down attention. Trends Neurosci. 34, 210–224 (2011).
Fosque, B. F. et al. Neural circuits. Labeling of active neural circuits in vivo with designed calcium integrators. Science 347, 755–760 (2015).
Zhang, S. et al. Selective attention. Long-range and local circuits for top-down modulation of visual cortex processing. Science 345, 660–665 (2014).
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).
Miller, E. K. & Buschman, T. J. Cortical circuits for the control of attention. Curr. Opin. Neurobiol. 23, 216–222 (2013).
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).
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).
Higgins, G. A. & Breysse, N. Rodent model of attention: the 5-choice serial reaction time task. Curr. Protocols Pharmacol. Chapter 5, 49 (2008).
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).
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).
Uchida, N. & Mainen, Z. F. Speed and accuracy of olfactory discrimination in the rat. Nat. Neurosci. 6, 1224–1229 (2003).
Jaramillo, S. & Zador, A. M. The auditory cortex mediates the perceptual effects of acoustic temporal expectation. Nat. Neurosci. 14, 246–251 (2011).
Ahrens, S. et al. ErbB4 regulation of a thalamic reticular nucleus circuit for sensory selection. Nat. Neurosci. 18, 104–111 (2015).
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).
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).
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).
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).
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).
Spencer, S. J. et al. Ghrelin regulates the hypothalamic-pituitary-adrenal axis and restricts anxiety after acute stress. Biol. Psychiatry 72, 457–465 (2012).
Tu, W. et al. DAPK1 interaction with NMDA receptor NR2B subunits mediates brain damage in stroke. Cell 140, 222–234 (2010).
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).
Zeng, W. B. et al. Anterograde monosynaptic transneuronal tracers derived from herpes simplex virus 1 strain H129. Mol. Neurodegener. 12, 38 (2017).
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).
Del Pino, I. et al. Abnormal wiring of CCK+ basket cells disrupts spatial information coding. Nat. Neurosci. 20, 784–792 (2017).
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).
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).
Hitti, F. L. & Siegelbaum, S. A. The hippocampal CA2 region is essential for social memory. Nature 508, 88–92 (2014).
Feng, S. et al. Canonical transient receptor potential 3 channels regulate mitochondrial calcium uptake. Proc. Natl. Acad. Sci. USA 110, 11011–11016 (2013).
Sugiyama, T., Osumi, N. & Katsuyama, Y. A novel cell migratory zone in the developing hippocampal formation. J. Comp. Neurol. 522, 3520–3538 (2014).
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).
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).
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
Authors and Affiliations
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
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
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
About this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41593-018-0207-0
This article is cited by
-
Acute exposure of microwave impairs attention process by activating microglial inflammation
Cell & Bioscience (2024)
-
Plastic and stimulus-specific coding of salient events in the central amygdala
Nature (2023)
-
Distribution Patterns of Subgroups of Inhibitory Neurons Divided by Calbindin 1
Molecular Neurobiology (2023)
-
A Novel Mouse Model for Polysynaptic Retrograde Tracing and Rabies Pathological Research
Cellular and Molecular Neurobiology (2023)
-
miR-34b-3p Inhibition of eIF4E Causes Post-stroke Depression in Adult Mice
Neuroscience Bulletin (2023)