Section on Light and Circadian Rhythms

National Institute Of Mental Health

Investigators

Linked publications & trials

Abstract

Research projects, Fiscal Year 2025, 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. 2- 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). In collaboration with Dr. Hugo Tejeda, we made progress in understanding how this brain region interacts with downstream regions to influence mood and recently published this work. A new collaboration with the Chudasama lab is going to determine if this region is found in primates and hopefully future collaboration in humans. 3- Perhaps one of the most exciting aspects of modern neuroscience is to understand the exact circuits that drive behaviors. We recently used genetic techniques to label only a single ipRGC subtype and determine its role in vision regulation. This work is now in review in Cell press. 4- We are interested in how the circadian system and stress interact. In understanding this novel area, we homed in on the paraventricular nucleus of the thalamus and its interaction with the SCN. This work was recently published in Science advances. 5- In a startling discovery we now show that there is a homeostatic retinal gate and an SCN circadian gate interacting to allow organisms to photoentrain properly to the light dark cycles. We propose that the ipRGC-SCN form an integrated pacemaker under physiological conditions. 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.