Research projects carried during the Fiscal Year 2017 1- Contribution of rod/cone photoreceptors to non-image functions: In 2010, we published that rods and melanopsin phototransduction are complementary for signaling light to circadian photoentrainment (Altimus et al., Nature Neurosci 2010) and recently we showed the same for the Pupillary light reflex (Keenan et al., eLife 2016). We have now begun to determine the contribution of rods and cones to other non-image behaviors including acute body temperature regulation. We found that the retinal circuits that underlie the effects of light on body temperature regulation are distinct from those for circadian photoentrainment and we are in the process of determining why these differences exist by using the new behavioral setup that is being built at NIMH. 2- Defining the retinal and brain circuits that drive circadian photoentrainment and phase shifts: We have generated genetically modified mouse lines to uncover the contribution of ipRGC subtypes 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either harbor only the SCN-projecting ipRGCs (Chen et al., Nature 2011) or lack the ipRGCs that project to the SCN (unpublished).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. 3- Molecular and functional characterization of the 200 M1-Brn3b-negative ipRGCs: 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 using our resources at NIMH. 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. 4- SCN-neuropeptides in regulating light-mediated effects on sleep: The SCN is believed to influence circadian rhythms primarily by direct efferent connections with downstream brain regions. The SCN produces several neuropeptides including vasoactive intestinal peptide (VIP), gastrin releasing peptide (Grp), prokineticin-2 (Prok2), and arginine-vasopressin (Avp). These neuropeptides are thought to synchronize cellular oscillators within the SCN. However, whether they are capable of entraining downstream oscillators is unclear. A major obstacle to the study of SCN neuropeptide functions in controlling downstream oscillators has been the availability of animal models that still have SCN synchrony but lack neuropeptide expression. We have generated a mouse model that lacks the expression of major SCN neuropeptides but maintains synchronous cellular oscillations in the SCN. This allows us, for the first time, to specifically address the necessity and sufficiency of SCN neuropeptides in regulating circadian behaviors. In collaboration with Seth Blackshaw (Johns Hopkins School of Medicine), we conditionally deleted a LIM homeodomain transcription factor, Lhx1, specifically in the SCN (Six3-Cre;Lhx1lox/lox henceforth called Lhx1 mutant mice). We found that Lhx1-mutants exhibit a dramatic downregulation in the levels of the major SCN neuropeptides, Vip, Grp, Avp and Prok2. Notably, the maturation of SCN, the core SCN clock-work and clock-controlled gene expression are still preserved (Bedont et al., Cell Reports 2014). Lhx1-mutant mice exhibit modest deficits in the circadian output behavior of wheel running activity, but importantly, we observed profound deficits in sleep regulation by light (Bedont et al., Current Biology 2017). We will determine the necessity of the SCN neuropeptides in controlling sleep. 5. An Lhx6-neuronal population regulates sleep In an exciting collaboration with Seth Blackshaw's lab, we found an undefined population of Lhx-6 GABA neurons in the zona incerta regulate sleep (Liu, Nature 2017). 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
Duy, Phan Q; Hattar, Samer (2017) Chronic Circadian Misalignment without Circadian Arrhythmicity or Sleep Deprivation Does Not Impair Adult Hippocampal Neurogenesis. J Biol Rhythms 32:621-626
Chen, Chih-Ming; Orefice, Lauren L; Chiu, Shu-Ling et al. (2017) Wnt5a is essential for hippocampal dendritic maintenance and spatial learning and memory in adult mice. Proc Natl Acad Sci U S A 114:E619-E628
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

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