Mood, the Circadian System, and Melanopsin Retinal Ganglion Cells

Abstract

The discovery of a third type of photoreceptors in the mammalian retina, intrinsically photosensitive retinal ganglion cells (ipRGCs), has had a revolutionary impact on chronobiology. We can now properly account for numerous non-vision-related functions of light, including its effect on the circadian system. Here, we give an overview of ipRGCs and their function as it relates specifically to mood and biological rhythms. Although circadian disruptions have been traditionally hypothesized to be the mediators of light's effects on mood, here we present an alternative model that dispenses with assumptions of causality between the two phenomena and explains mood regulation by light via another ipRGC-dependent mechanism.

Keywords: circadian; ipRGC; light; mood; photoperiod; rhythms.

Figure 1

The molecular clock in every cell consists of reciprocal positive and negative feedback loops. CLOCK and BMAL1 form heterodimers that activate the transcription of Cry and Per genes. PER dimerizes with CRY to inhibit CLOCK-BMAL1–mediated transcription. The timing of dimerization, complex formation, and translocation into the nucleus determines the cellular rhythms. Abbreviations: Ccg, clock controlled gene; CK1ε/δ, casein kinase 1ε/δ; CRY, cryptochrome; E-box, enhancer-box; PER, period; ROR, retinoic acid–related orphan receptor; RORE, RevDR2 and ROR-binding element. Figure adapted from Takahashi (2017).

Figure 2

The mammalian brain teems with circadian oscillators. The SCN is the master pacemaker. Semiautonomous oscillators, such as the LHb, contain cells individually characterized by rhythmic activity, but only the input from a master oscillator can synchronize them into a coherent, nucleus-wide rhythm. Finally, slave oscillators, such as the BNST, display rhythms only in response to input from other oscillators. Abbreviations: ARC, arcuate nucleus; BNST, bed nucleus of the stria terminalis; DMH, dorsomedial hypothalamus; LHb, lateral habenula; OB, olfactory bulb; SCN, suprachiasmatic nucleus. Figure adapted from Guilding & Piggins (2007).

Figure 3

Photoperiod history calculation based on differential speed of entrainment to an increase in daylength. The plots represent the output of two different circadian oscillators. The first row shows the state of the system in a constant short [e.g., light:dark (LD) 8:16 h] photoperiod (framed in blue); on day 0, the animal is switched from a short to a long (e.g., LD 16:8) photoperiod. The bottom row shows the state of the system after both oscillators have entrained to the new photoperiod (framed in yellow). The middle row shows the transient state during which a discordance arises between the two.

Figure 4

ipRGC signaling affects both circadian rhythms and mood. This diagram illustrates how the two phenomena can appear correlated while not being causally linked. Circadian oscillators of the brain orchestrate the circadian rhythms of physiology and behavior directly, but mood is affected by a comparison of incidental properties of their output. Abbreviation: ipRGC, intrinsically photosensitive retinal ganglion cell.