Section on Light and Circadian Rhythms

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Research projects, Fiscal Year 2020, can be divided into four major areas listed below: 1- Diversity and function of ipRGCs We have generated genetically modified mouse lines to uncover the contribution of intrinsically photosensitive retinal ganglion cells (ipRGCs) and the corresponding brain circuits to the synchronization of the internal biological clock to the solar day. We have animals that either harbor only the suprachiasmatic nucleus (SCN)-projecting ipRGCs (Chen et al., Nature 2011) or we are generating animals that lack the ipRGCs that project to the SCN. This will allow us to determine the contribution of individual subtypes of ipRGCs to circadian photoentrainment and phase shifts. The phase of the circadian oscillator can be advanced or delayed by acute pulses of light, known as phase shifts. We have a recently accepted paper that reveals that different brain circuits control phase delays versus phase advances in the circadian oscillator. This finding challenges the current view in the field that similar mechanisms underlie phase advances and phase delays, and that light has a simple on/off effect on the clock. We are currently preparing a manuscript for publication which will determine the ipRGC populations that are necessary for changes in the phase of the circadian clock, and map the brain regions that underlie these functions. We recently made a startling discovery that a subpopulation of ipRGCs (200 M1-Brn3b-negative, which we called circadian photoreceptors) is critical for the development of the circadian clock as well as vision, although they do not project to visual centers (Chew et al., eLife 2017). An exciting hypothesis is that these 200 ipRGCs (Chen et al., Nature 2011) represent an evolutionarily ancient photoreceptor class given their broad influence on several distinct behaviors (photoentrainment, development of the clock and vision as well as local pupillary light reflex). Therefore, it is critical to understand the molecular and functional specification of this population in relation to other ipRGCs and conventional ganglion cells. Thus, we obtained data in collaboration with Alex Kolodkins lab at the Johns Hopkins University-School of Medicine for the transcriptome of this population. This project will provide the molecular handles to understand the ontogeny and the functional specialization of the 200 M1 ipRGCs in relation to other ipRGCs and conventional ganglion cells. 2- Uncovering the retinal and brain circuits that underlies the influence of light to mood and learning and memory It is well established that light therapy can be used to treat several types of major depression in humans. However, it has been hard to ascertain whether these effects of light are purely placebo effects. We recently published an exciting brain region involved in mediating light effects on mood (Fernandez et. al., Cell 2018). We started collaborating with Dr. Hugo Tejeda to understand how this brain region interacts with downstream regions to influence mood. Future collaborations are established with the labs of Drs. Chudasama and Merikangas to determine if this region is found in primates, including humans. 3- Determining how light influences sleep regulation through a direct pathway or through the circadian photoentrainment mechanism An unanswered question in the field of sleep is whether light required for circadian photoentrainment uses the same circuits as those required for the acute effects of light on sleep. We recently published that the SCN is dispensable for such effects (Rupp et. al., Elife 2019). We discovered that the Brn3b-negative ipRGCs that project to the SCN are sufficient for photoentraining sleep rhythms. Remarkably, these cells are not capable of inducing acute effects of light on sleep. In fact, we show that cells other than the ipRGCs that project to the SCN are required (Rupp et. al., Elife 2019). We now have a paper in review that uncovers the brain region that is required for the effects of light on sleep. 4- Retina and ipRGCs influence timed feeding Perhaps one of the most surprising discoveries of this year was the recognition that the retina and ipRGCs are required for timed feeding. This work in collaboration with Mario Penzo is now published in Nature. Together, we will continue to break new ground about how light signaling from the environment regulates several functions that are essential for the well-being of humans. 3- Determining how light influences sleep and body temperature regulation through a direct pathway or through the circadian photoentrainment mechanism. An unanswered question in the fields ofbody temperature regulation and sleep is whether, light required for circadian photoentrainment uses the same circuits as light required for the acute effects of light on these two functions. We used mice in this study (Rupp et. al., Elife 2019), which are nocturnal, which means that light induces sleep and lower body temperature acutely as compared to alertness and increase in body temperature in humans. We discovered that the Brn3b-negative ipRGCs that project to the SCN are sufficient for photoentraining both body temperature and sleep rhythms. Remarkably, these cells are not capable of inducing acute effects of light on either function. In fact, we show that cells other than the ipRGCs that project to the SCN are required (Rupp et. al., Elife 2019). Future studies will aim to define the brain regions required for the acute light effects on body temperature and sleep. 4- Other projects as collaborations Three other projects were published as collaborations. First, with Dr. Yoshimuras group in Japan, we showed that a new neuropsin 5 has a role in circadian photoentrainment under UV light stimulations. Second, with Dr. Johnstons lab at the Johns Hopkins University, our Co-student, Kiara Eldred, was able to generate human retina in culture and figure out the pathway by which blue versus red/green cones are generated. Third with Dr. Parks lab at the University of Miami, we figured out why ipRGCs are more resistant to cells death and have better regenerating abilities compared to other RGCs. Together, we will continue to break new ground about how light signaling from the environment regulates several functions that are essential for the well-being of humans.