Rod photoreceptors drive circadian photoentrainment across a wide range of light intensities

Journal name:
Nature Neuroscience
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Published online


In mammals, synchronization of the circadian pacemaker in the hypothalamus is achieved through direct input from the eyes conveyed by intrinsically photosensitive retinal ganglion cells (ipRGCs). Circadian photoentrainment can be maintained by rod and cone photoreceptors, but their functional contributions and their retinal circuits that impinge on ipRGCs are not well understood. Using mice that lack functional rods or in which rods are the only functional photoreceptors, we found that rods were solely responsible for photoentrainment at scotopic light intensities. Rods were also capable of driving circadian photoentrainment at photopic intensities at which they were incapable of supporting a visually guided behavior. Using mice in which cone photoreceptors were ablated, we found that rods signal through cones at high light intensities, but not at low light intensities. Thus, rods use two distinct retinal circuits to drive ipRGC function to support circadian photoentrainment across a wide range of light intensities.

At a glance


  1. Rods drive circadian photoentrainment across a wide range of light intensities.
    Figure 1: Rods drive circadian photoentrainment across a wide range of light intensities.

    (a) Retinal schematics for all transgenic mouse lines used; gray represents the functional photoreceptor, black represents the nonfunctional resembling dark state and the striped area represents the nonfunctional resembling saturating light state. R, rod photoreceptors; C, cone photoreceptors; RB, rod bipolar cells; CB, cone bipolar cells. (bf) Representative double-plotted wheel-running activity records for wild-type (b), Gnat1−/− (c), rod-only type 1 (d), rod-only type 2 (e) and rod-only type 3 (f) mice assaying for photoentrainment to a 12-h:12-h light:dark cycle that advances 6 h concurrently with each intensity decrease. Local time is indicated at the top of each graph and light intensity (lux) is indicated along y axis of each actogram. Mice were exposed to a 6-h advanced cycle before the start of this experiment. Note the re-entrainment time course at the 500 lx intensity in all mice which were able to photoentrain (b,c,e, but not d,f). DD, constant dark (0 lx). (g) Summary of percentage of photoentrained mice for all genotypes. Refer to Table 1 for the number of mice and statistics for each genotype at each light intensity.

  2. The rod-cone pathway is important for mesopic light signaling.
    Figure 2: The rod-cone pathway is important for mesopic light signaling.

    (a) Representative traces from current-clamp recordings of membrane potential as a function of time from rod bipolar, off bipolar and horizontal cells of wild-type, rod-only type 1, rod-only type 2 and rod-only type 3 mice showing that rod input to each cell type was intact. Arrow represents timing of a 10-ms flash whose strength was increased by a factor of 2 from generating a just-detectable response to response saturation. Flash strengths for all cells ranged from 0.2 to 30 activated rhodopsins (R*) per rod. Vertical scale bars represent 10 mV; horizontal axes, time in seconds. (b) The spatial frequency threshold (cycles per degree) of mice lacking rod function (Gnat1−/−) was comparable to that of wild-type mice at photopic light intensities, whereas the spatial frequency threshold of rod-only type 1, rod-only type 2 and rod-only type 3 mice was equivalent to that seen in wild-type mice in scotopic light. Rod-only type 2 mice, but not rod-only type 1 and rod-only type 3 mice, showed similar visual function to wild type at mesopic light levels. Note that all rod-only mice failed to track at photopic light intensities, whereas Gnat1−/− mice did not track at scotopic light intensities. Error bars represent s.e.m. RO1, rod-only type 1; RO2, rod-only type 2; RO3, rod-only type 3; WT, wild type.

  3. Rods contribution to phase shifts and period lengthening in constant light is dependent on cone state.
    Figure 3: Rods contribution to phase shifts and period lengthening in constant light is dependent on cone state.

    (a) Wild-type, Gnat1−/− and rod-only type 2 mice responded similarly to 15-min, 1,000-lx white-light pulse administered at CT16 (Circadian Time 16), whereas rod-only type 1 and rod-only type 3 mice showed minimal shift in activity onset. (b) Period length in constant darkness was compared to period length in constant light in all mice. Wild-type, Gnat1−/− and rod-only type 2 mice all showed significant period lengthening in constant light; however, rod-only type 2 period length in constant light was significantly shorter than that seen in wild-type mice. Rod-only type 1 and 3 mice showed no significant period lengthening in constant light. *P < 0.05, **P < 0.01. Error bars represent s.e.m.


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Author information


  1. Department of Biology, Johns Hopkins University, Baltimore, Maryland, USA.

    • Cara M Altimus,
    • Ali D Güler &
    • Samer Hattar
  2. Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, New York, USA.

    • Nazia M Alam &
    • Glen T Prusky
  3. Zilkha Neurogenetic Institute, Department of Physiology and Biophysics, University of Southern California Keck School of Medicine, Los Angeles, California, USA.

    • A Cyrus Arman &
    • Alapakkam P Sampath
  4. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Samer Hattar


The experiments were conceived and designed by C.M.A., A.D.G., A.P.S. and S.H. Wheel-running experiments were carried out by C.M.A. A.C.A. performed current-clamp recordings of retinal cells. N.M.A., C.M.A. and G.T.P. carried out virtual optomotor system experiments. C.M.A., A.D.G., A.P.S. and S.H. wrote the manuscript, which was reviewed and edited by all of the authors.

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