To the mammalian eye, light offers more than just sight. “Light is so important for many innate functions,” says neuroscientist Samer Hattar of the National Institute of Mental Health (NIMH). “We really don’t appreciate the importance of light in our lives.”
The effect of light on mood is especially far reaching—from light-related mood disorders such as seasonal affective disorder, to the depressive symptoms that can accompany jet lag and shift work. Now, Hattar’s team has uncovered the distinct pathways in mice from the retina to the brain that drive the effects of light on mood as well as learning. The findings, reported in Cell, could point to targets for future therapies for light-related mood disorders.
In the 2000’s, Hattar, in collaboration with Brown University’s David Berson and alongside work by University of Virginia’s Ignacio Provencio, helped to reveal that the retina houses not only the long-recognized rod and cone cells necessary for vision but also a third cell type that uses light as a cue for regulating circadian rhythms and sleep. In 2012, Hattar’s group showed that this third group, known as intrinsically photosensitive retinal ganglion cells (ipRGCs), is also responsible for light’s effects on mood and learning in mice.
IpRGCs connect to many brain regions. But a subset extend directly to the hypothalamic suprachiasmatic nucleus (SCN), the same region that controls circadian rhythms. For the recent study, Hattar’s team first tested whether these particular ipRGCs might be the conduits for light’s effect on learning using a mouse line in which only this subset of ipRGCs functions.
Under light conditions that approximate a normal day-night cycle, these test mice showed similar cognitive functions as control mice. Both groups, for example, had similar interest in investigating novel objects, and both performed similarly well on the Morris water maze, a spatial learning challenge.
The team then exposed the mice to alternating 3.5-hour periods of light and dark. Both control and test mice responded to this light disruption with poorer performances on the cognitive function tests, demonstrating that the ipRGCs extending to the SCN can mediate the light-induced learning difficulties.
The team then tested whether this same subset of ipRGCs also helps drive light’s effect on mood. The researchers again placed the two groups of mice under normal and altered light cycles. In each light environment, they administered the sucrose preference test, in which a lack of preference for sweetened water suggests an inability to feel pleasure. The researchers also performed two tests that assess depression-like behavior by quantifying how quickly a mouse gives up in a stressful situation.
Under normal light conditions, the test and control mice fared similarly. But in the disrupted light environment, the control mice showed depression-like behavior while the test mice were unaffected, suggesting that a different subset of ipRGCs must be responsible for light’s effect on mood.
To identify these ipRGCs and trace their path through the brain, the team probed mouse neural circuits using a series of fluorescent tracers and fiber photometry techniques. They identified ipRGCs that extend to a region that they call the perihabenular nucleus, which they learned is part of the thalamus and targets numerous previously recognized mood regulating centers. By experimentally perturbing this pathway in mice under normal and altered light cycles, the team confirmed its role in driving the effect of light on mood.
The team’s methods are “a real tour de force,” says neuroscientist Colleen McClung of the University of Pittsburgh School of Medicine, who was not involved in the study. “They do a really thorough job of identifying this particular circuitry.”
“This is the first paper that I’ve seen that really convincingly maps the initial response to light from cells within our eyes and connects it to a mood center in the brain,” says neuroscientist Scott Russo of the Icahn School of Medicine at Mount Sinai. “What would be interesting in the future, would be to think about what types of drugable molecules could impact these circuits.”
Still, Russo notes that it isn’t yet clear whether these findings could translate into treatments for light-related mood disorders. As for all such studies, it’s hard to know whether a mouse displaying what appears to be depressive behavior is truly depressed in a human sense. And as McClung notes, just “because a circuit is found in a mouse, doesn’t mean it automatically will be the same circuitry in humans.”
In hopes of opening the door to clinical applications, Hattar is currently collaborating with others at NIMH to design fMRI studies that could reveal whether these same circuits are present and responsive to light in humans.