Section on Light and Circadian Rhythms

National Institute Of Mental Health

Investigators

Linked publications, trials & patents

Abstract

Research projects, Fiscal Year 2021, can be divided into four major areas listed below: 1- How rods and cones drive behaviors through 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 used viruses to block input from non-SCN regions keeping the ipRGCs that project to the SCN intact. We found different contributions of individual subtypes of ipRGCs to circadian photoentrainment. Remarkably, the rod/cone input requires areas distinct from the SCN for photoentrainment. Specifically, Brn3b-negative ipRGCs do not support rod/cone input, whereas Brn3b-positive ipRGCs are predominantly important for rod/cone input. We are currently preparing a manuscript for publication for this important discovery. We 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 Kolodkin's 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. Finally, 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. In addition, since this mood center receives predominant input from Brn3b-positive ipRGCs, we will determine whether rod/cone input to this region is important for mood regulation. 2- Define new sleep areas that are modulated by light input. 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 accepted in Nature Communications that uncovers the brain region that is required for the effects of light on sleep. This region is part of the preoptic region and projects to wakefulness centers. 3- Understand the developmental program for retinal ganglion cells. A dogma in textbooks indicates that Atonal 7 (Atoh7) is the master transcription factor that specifies all RGCs in mammals. We have shown recently that the story is much more elaborate than that. In a paper we published in Science Advances, we reveal that only 50% of RGCs are truly dependent on Atoh7 for specification. Other ganglion cells require Atoh7 in a cell non-autonomous fashion for survival. 4-Decipher the differential input from ipRGCs and conventional RGCs to different brain regions. How do ipRGCs and RGCs target different brain regions to influence behavior? In a tour de force approach, we were able to label the ipRGCs and the RGCs separately and show how they target different brain regions. We discovered that in addition to the SCN, a ventral region in the visual thalamus receives exclusive input from ipRGCs. This opens a new area to try to understand the role of this region in non-image forming visual functions. 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.