Aberrant light conditions experienced during shift-work and transmeridian travel, as well as seasonal changes in day length, cause mood and cognitive deficits. The prevailing view is that these behavioral effects arise from disruptions in sleep and circadian rhythms. However, we have recently shown that aberrant light schedules directly lead to mood and cognitive deficits. The mammalian retina, which contains three major photoreceptors, rods, cones, and intrinsically photosensitive retinal ganglion cells (ipRGCs), is the site of light detection for all light-dependent behaviors. The ipRGCs express the photopigment melanopsin and respond to light both intrinsically via the melanopsin photopigment but also extrinsically through rod/cone circuitry, similar to conventional RGCs. Furthermore, ipRGCs project to a variety of brain regions that include the master circadian pacemaker as well as areas that have been implicated in mood and affect regulation. We have identified ipRGCs as a critical node in the circuit underling the direct effects of disruptive ligh schedule on mood and cognition. In this proposal, our major goals are to identify the retinal circuits and the brain targets that are necessary for aberrant light to cause mood and learning deficits. Specifically, we have several retinal mouse mutants that will allow us to delineate the relative contributions of the intrinsic melanopsin-based phototransduction versus the extrinsic rod/cone input to the disruptive effects of aberrant light on mood and cognition. In addition, we have generated multiple mouse lines where we have either specifically ablated or specifically retained a subset of ipRGCs that project to the master circadian pacemaker and drive circadian photoentrainment. To identify brain regions that are sufficient for the negative effects of aberran light, we will specifically activate ipRGC terminals using optogenetics, to mimic the effects of aberrant light on individual brain regions. The combination of mutant mouse lines with this optogenetic approach will allow us to begin to identify the circuits that mediate how aberrant light schedules lead to mood and learning deficits. The findings obtained from this proposal will provide a basis to design better lighting environments at homes, schools and work environment to improve mood and cognition leading to increased productivity. In addition, the identification of new brain circuits that impinge on mood regulation will provide new neuronal targets for the better use of light for therapeutic purposes.
Irregular light schedules due to travel across time zones and shift work cause several deficits in mood and cognition which include depression, difficulty concentrating, lack of energy and sleep problems, and seasonal shifts in day length result in a form of depression known as seasonal affective disorder or SAD. This project expands on our recent surprising discovery that aberrant light directly influences mood and learning through a new type of photoreceptor cells (known as ipRGCs), independent of sleep and circadian disruptions. Since these ipRGCs project to a wide range of brain regions, the goal of this proposal is to delineate the neuronal pathways whereby light directly influences mood-related behaviors, to gain insight into the mechanisms underlying depression, and to provide essential knowledge required for devising better home and work lighting environments to reduce or even eliminate the negative effects of aberrant light on mood and cognition.
|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|
|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|
|Keenan, William Thomas; Rupp, Alan C; Ross, Rachel A et al. (2016) A visual circuit uses complementary mechanisms to support transient and sustained pupil constriction. Elife 5:|
|Gompf, Heinrich S; Fuller, Patrick M; Hattar, Samer et al. (2015) Impaired circadian photosensitivity in mice lacking glutamate transmission from retinal melanopsin cells. J Biol Rhythms 30:35-41|
|LeGates, Tara A; Fernandez, Diego C; Hattar, Samer (2014) Light as a central modulator of circadian rhythms, sleep and affect. Nat Rev Neurosci 15:443-54|
|Bedont, Joseph L; LeGates, Tara A; Slat, Emily A et al. (2014) Lhx1 controls terminal differentiation and circadian function of the suprachiasmatic nucleus. Cell Rep 7:609-22|
|Joo, Hannah R; Peterson, Beth B; Dacey, Dennis M et al. (2013) Recurrent axon collaterals of intrinsically photosensitive retinal ganglion cells. Vis Neurosci 30:175-82|