198 | Nature | Vol 581 | 14 May 2020
Article
These results demonstrate that the signalling of IGLNPY neurons project-
ing specifically to SCN is required for entrainment to TRF.
Discussion
Here we reveal that early innervation by ipRGCs affects the assembly
of a functional IGLNPY–SCN circuit. Moreover, the correct assembly of
this circuit is necessary for the circadian anticipatory responses that
are associated with TRF in adult mice.
The integration of environmental cues occurs widely in the nervous
system. It has been extensively documented that early ablation of reti-
nal input to the superior colliculus—a major node of multisensory inte-
gration^23 —leads to an extensive rewiring of its sensory inputs^24 , causing
the strengthening of responses to nonvisual stimuli^25 ,^26. On the basis of
these results, our original expectation was that ablating the innervation
by ipRGCs to brain centres would cause a strengthening of circadian
entrainment to nonphotic modalities. Our results show a weakening
of nonphotic entrainment in mice that lack early retinal innervation
to brain targets. Therefore, we propose that the retina–IGLNPY–SCN
circuits do not follow the conventional model of early plasticity that
has been described for the image-forming visual system.
Feeding behaviour is the result of the integration of multiple
responses to food, including energy homeostasis^27 , hedonic reward^28
and memory traces^29 , as well as anticipation to timed food availability
driven by a food-entrainable oscillator^30 ,^31. Our results suggest that
IGLNPY neurons require retinal innervation to the SCN during early devel-
opment for normal circuit assembly, and act as a node of connection
between the food-entrainable-oscillator network and the central pace-
maker of the SCN in adult mice (Extended Data Fig. 8, Supplementary
Discussion).
Online content
Any methods, additional references, Nature Research reporting sum-
maries, source data, extended data, supplementary information,
acknowledgements, peer review information; details of author con-
tributions and competing interests; and statements of data and code
availability are available at https://doi.org/10.1038/s41586-020-2204-1.
- Golombek, D. A. & Rosenstein, R. E. Physiology of circadian entrainment. Physiol. Rev. 90 ,
1063–1102 (2010). - Cappe, C., Rouiller, E. M. & Barone, P. in The Neural Bases of Multisensory Processes (eds
Murray, M. M. & Wallace, M. T.) Chapter 2 (CRC, 2012). - Mahoney, J. R. et al. Keeping in touch with the visual system: spatial alignment and
multisensory integration of visual-somatosensory inputs. Front. Psychol. 6 , 1068 (2015). - Güler, A. D. et al. Melanopsin cells are the principal conduits for rod-cone input to
non-image-forming vision. Nature 453 , 102–105 (2008).
5. Hattar, S., Liao, H. W., Takao, M., Berson, D. M. & Yau, K. W. Melanopsin-containing retinal
ganglion cells: architecture, projections, and intrinsic photosensitivity. Science 295 ,
1065–1070 (2002).
6. Berson, D. M., Dunn, F. A. & Takao, M. Phototransduction by retinal ganglion cells that set
the circadian clock. Science 295 , 1070–1073 (2002).
7. Saderi, N. et al. The NPY intergeniculate leaflet projections to the suprachiasmatic
nucleus transmit metabolic conditions. Neuroscience 246 , 291–300 (2013).
8. Moore, R. Y. & Card, J. P. Intergeniculate leaflet: an anatomically and functionally distinct
subdivision of the lateral geniculate complex. J. Comp. Neurol. 344 , 403–430 (1994).
9. Morin, L. P. Neuroanatomy of the extended circadian rhythm system. Exp. Neurol. 243 ,
4–20 (2013).
10. Wams, E. J., Riede, S. J., van der Laan, I., ten Bulte, T. & Hut, R. A. in Biological Timekeeping:
Clocks, Rhythms and Behaviour (ed. Kumar, V.) 395–404 (Springer India, 2017).
11. Chew, K. S. et al. A subset of ipRGCs regulates both maturation of the circadian clock and
segregation of retinogeniculate projections in mice. eLife 6 , e22861 (2017).
12. Mistlberger, R. E. Food-anticipatory circadian rhythms: concepts and methods. Eur. J.
Neurosci. 30 , 1718–1729 (2009).
13. Acosta-Galvan, G. et al. Interaction between hypothalamic dorsomedial nucleus and the
suprachiasmatic nucleus determines intensity of food anticipatory behavior. Proc. Natl
Acad. Sci. USA 108 , 5813–5818 (2011).
14. Patton, D. F. et al. Photic and pineal modulation of food anticipatory circadian activity
rhythms in rodents. PLoS ONE 8 , e81588 (2013).
15. Nakazato, M. et al. A role for ghrelin in the central regulation of feeding. Nature 409 ,
194–198 (2001).
16. Camiña, J. P. et al. Regulation of ghrelin secretion and action. Endocrine 22 , 5–12 (2003).
17. Blum, I. D., Lamont, E. W., Rodrigues, T. & Abizaid, A. Isolating neural correlates of the
pacemaker for food anticipation. PLoS ONE 7 , e36117 (2012).
18. Glass, J. D., Guinn, J., Kaur, G. & Francl, J. M. On the intrinsic regulation of neuropeptide Y
release in the mammalian suprachiasmatic nucleus circadian clock. Eur. J. Neurosci. 31 ,
1117–1126 (2010).
19. Andermann, M. L. & Lowell, B. B. Toward a wiring diagram understanding of appetite
control. Neuron 95 , 757–778 (2017).
20. Chen, S.-K., Badea, T. C. & Hattar, S. Photoentrainment and pupillary light reflex are
mediated by distinct populations of ipRGCs. Nature 476 , 92–95 (2011).
21. Fernandez, D. C. et al. Light affects mood and learning through distinct retina–brain
pathways. Cell 175 , 71–84.e18 (2018).
22. Sindelar, D. K., Palmiter, R. D., Woods, S. C. & Schwartz, M. W. Attenuated feeding
responses to circadian and palatability cues in mice lacking neuropeptide Y. Peptides 26 ,
2597–2602 (2005).
23. May, P. J. The mammalian superior colliculus: laminar structure and connections. Prog.
Brain Res. 151 , 321–378 (2006).
24. Gandhi, N. J. & Katnani, H. A. Motor functions of the superior colliculus. Annu. Rev.
Neurosci. 34 , 205–231 (2011).
25. Stein, B. E., Stanford, T. R. & Rowland, B. A. Development of multisensory integration from
the perspective of the individual neuron. Nat. Rev. Neurosci. 15 , 520–535 (2014).
26. Mundiñano, I. C. & Martínez-Millán, L. Somatosensory cross-modal plasticity in the
superior colliculus of visually deafferented rats. Neuroscience 165 , 1457–1470 (2010).
27. Waterson, M. J. & Horvath, T. L. Neuronal regulation of energy homeostasis: beyond the
hypothalamus and feeding. Cell Metab. 22 , 962–970 (2015).
28. Sheng, Z., Santiago, A. M., Thomas, M. P. & Routh, V. H. Metabolic regulation of lateral
hypothalamic glucose-inhibited orexin neurons may influence midbrain reward
neurocircuitry. Mol. Cell. Neurosci. 62 , 30–41 (2014).
29. Azevedo, E. P. et al. A role of Drd2 hippocampal neurons in context-dependent food
intake. Neuron 102 , 873–886.e5 (2019).
30. Challet, E. The circadian regulation of food intake. Nat. Rev. Endocrinol. 15 , 393–405 (2019).
31. Pendergast, J. S. & Yamazaki, S. The mysterious food-entrainable oscillator: insights from
mutant and engineered mouse models. J. Biol. Rhythms 33 , 458–474 (2018).
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
© The Author(s), under exclusive licence to Springer Nature Limited 2020