Research projects, Fiscal Year 2019, 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suprachiasmatic nucleus (SCN)-projecting ipRGCs (Chen et al., Nature 2011) or lack the ipRGCs that project to the SCN (unpublished). 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. Our exciting preliminary data reveal that different populations of ipRGCs 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. Future studies will determine which ipRGC populations are necessary for advances versus delays, and map the brain regions that are influenced by light to cause changes in the phase of the circadian oscillator. 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 evolutionary 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 have started to examine the transcriptome and epigenetic marks of this population by using the intramural sequencing facilities. 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. This is being done in collaboration with Alex Kolodkins lab at the Johns Hopkins University-School of Medicine. 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 discovered a new brain region that allows light to directly regulate mood in rodents. This new region is termed the perihabenular complex and it connects to several areas in the brain essential for mood regulation such as the medial prefrontal cortex and the nucleus accumbens. This work has been published in Cell (Fernandez et. al., Cell 2018) and future collaborations are established with both Drs. Chudasama and Merikangas labs to determine if this region is found in primates, including humans. In the same publication, we also showed that the influence of light on learning and memory requires the SCN and specifically the Brn3b-negative ipRGCs. This is a remarkable separation between light effects on mood and learning. Incredibly, the SCN is not acting as a central pacemaker, but simply as a relay for light information to the hippocampus. Future work is aimed at figuring out this circuit(s). 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 of body 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.

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Tufford, Adele R; Onyak, Jessica R; Sondereker, Katelyn B et al. (2018) Melanopsin Retinal Ganglion Cells Regulate Cone Photoreceptor Lamination in the Mouse Retina. Cell Rep 23:2416-2428
Bedont, Joseph L; Rohr, Kayla E; Bathini, Abhijith et al. (2018) Asymmetric vasopressin signaling spatially organizes the master circadian clock. J Comp Neurol 526:2048-2067
Lu, Qi; Ganjawala, Tushar H; Hattar, Samer et al. (2018) A Robust Optomotor Assay for Assessing the Efficacy of Optogenetic Tools for Vision Restoration. Invest Ophthalmol Vis Sci 59:1288-1294
Fernandez, Diego Carlos; Fogerson, P Michelle; Lazzerini Ospri, Lorenzo et al. (2018) Light Affects Mood and Learning through Distinct Retina-Brain Pathways. Cell 175:71-84.e18
Mason, Ivy C; Boubekri, Mohamed; Figueiro, Mariana G et al. (2018) Circadian Health and Light: A Report on the National Heart, Lung, and Blood Institute's Workshop. J Biol Rhythms 33:451-457
Dellapolla, Adriano; Kloehn, Ian; Pancholi, Harshida et al. (2017) Long days enhance recognition memory and increase insulin-like growth factor 2 in the hippocampus. Sci Rep 7:3925
Chew, Kylie S; Renna, Jordan M; McNeill, David S et al. (2017) A subset of ipRGCs regulates both maturation of the circadian clock and segregation of retinogeniculate projections in mice. Elife 6:
Somasundaram, Preethi; Wyrick, Glenn R; Fernandez, Diego Carlos et al. (2017) C-terminal phosphorylation regulates the kinetics of a subset of melanopsin-mediated behaviors in mice. Proc Natl Acad Sci U S A 114:2741-2746
Liu, Kai; Kim, Juhyun; Kim, Dong Won et al. (2017) Lhx6-positive GABA-releasing neurons of the zona incerta promote sleep. Nature 548:582-587
Lazzerini Ospri, Lorenzo; Prusky, Glen; Hattar, Samer (2017) Mood, the Circadian System, and Melanopsin Retinal Ganglion Cells. Annu Rev Neurosci 40:539-556

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