The retina–brain unit

The idea

Light does far more than let us see. It sets our internal clocks, lifts or lowers mood, and sharpens attention and learning. The cells that carry this "non-image-forming" information are a specialized class of retinal neurons, the intrinsically photosensitive retinal ganglion cells (ipRGCs). Rather than feeding a single visual center, ipRGCs broadcast light throughout the brain. We study these projections not as isolated wires but as one integrated system: the retina–brain unit.

Retinal and brain circuits underlying the effects of light on non-image-forming visual functions. a. A schematic view of the retina showing the organization of different neuronal populations and their synaptic connections. Rods and cones are confined to the photoreceptor layer. Light detected by rods and cones is processed and signalled to retinal ganglion cells (RGCs) through horizontal, amacrine and bipolar cells. RGCs are the only output neurons from the retina to the brain. A subset of RGCs (4–5% of the total number of RCGs) are intrinsically photosensitive RGCs (ipRGCs). b. ipRGCs project to numerous brain regions, including many that have a role in driving light-mediated behaviours, including circadian photoentrainment and sleep. In addition, ipRGCs also innervate nuclei involved in depression and/or anxiety.

Modified from LeGates et al. Nat Rev Neurosci. 2014 .

Distinct pathways for mood and for learning

We found that separate subpopulations of ipRGCs drive light's effects on learning and on mood through distinct pathways. One population routes through the SCN to shape learning and memory — without disturbing the clock's timekeeping. A second, SCN-independent pathway led us to a previously unrecognized region of the thalamus, the perihabenular nucleus (PHb). The PHb sits within the brain's mood-regulating circuitry.

Chronically activating light-responsive PHb neurons in mice kept under a normal light cycle was enough on its own to produce mood deficits. Activating specifically the PHb neurons that project to the prefrontal cortex reproduced these mood effects while leaving learning and memory untouched, pinpointing the retina→PHb→prefrontal route as a dedicated mood pathway.

Conversely, silencing PHb output with tetanus toxin protected mice from the mood disturbances that an irregular light cycle would otherwise cause. Together, these manipulations show that the PHb doesn't merely respond to light — its activity is what converts disruptive light into altered mood.

Key discoveries and references

A single ipRGC innervates the entire SCN, and can do so bilaterally — explaining how the clock receives equal input from both eyes. (PNAS 2016)
Individual ipRGCs branch to up to five brain regions, broadcasting light widely rather than locally. (PNAS 2016)
Distinct ipRGC pathways separately control light's effects on learning and on mood. (Cell 2018)
Discovery of the perihabenular nucleus (PHb) — a new thalamic region necessary and sufficient for light-driven mood changes. (Cell 2018)
Non-invasive, chronic tools (eye-drop and drinking-water chemogenetics) to control these circuits in behaving animals. (JoVE 2019)

References:

Fernandez DC, Chang Y-T, Hattar S, Chen S-K. Architecture of retinal projections to the central circadian pacemaker. PNAS. 2016;113(21):6047–6052. https://doi.org/10.1073/pnas.1523629113
Fernandez DC, et al. Light Affects Mood and Learning through Distinct Retina-Brain Pathways. Cell. 2018;175(1):71–84. https://doi.org/10.1016/j.cell.2018.08.004
Zhan J, Komal R, Keenan WT, Hattar S, Fernandez DC. Non-invasive Strategies for Chronic Manipulation of DREADD-controlled Neuronal Activity. J Vis Exp. 2019;(150):e59439. https://doi.org/10.3791/59439