A Pathway for Circadian Regulation of Arousal is Functionally Important for Light-associated Depression



Aston-Jones Lab demonstrates that a pathway from the retina to the locus coeruleus is functionally important for light-associated mood changes

Unless you live in a low latitude region, you are probably well-aware of the winter blues. Having grown up in a place where clouds were seemingly non-existent, my first real winter was quite the rough experience. The notion that our mood can be so easily influenced by light exposure continues to fascinate me to this day.

Dr. Gary Aston-Jones’ group has been interested in the interplay between mood and light for quite some time. I had the pleasure of catching one of their posters on Sunday afternoon. Hannah Bowrey, one of the lab’s post-docs, gave me a wonderfully clear run-down of some of the group’s work. Almost two decades ago, Aston-Jones’ group characterized a pathway from the suprachiasmatic nucleus (SCN) that projects to the locus coeruleus (LC) via the dorsomedial hypothalamus (DMH). This circuit – which they refer to as the photic regulation of arousal and mood (PRAM) pathway – is thought to contribute to circadian regulation of arousal. This was supported by previous work demonstrating that disrupting circadian rhythms through light deprivation causes LC neurons – which are important for arousal – to degenerate. Interestingly, the animals also showed depressive-like behaviours. Thus, the question Bowrey’s poster posed was whether the PRAM pathway is implicated in depression.

Designer receptors exclusively activated by designer drugs (DREADDs) were expressed in rat retinas using a pan-neuronal promoter. This allowed the group to excite retinal ganglion cells (RGCs) by administering clozapine-N-oxide (CNO) intraperitoneally. Electroretinograms (ERG) analysis showed that RGCs were indeed depolarized by CNO. Noradrenergic neurons in the LC were also depolarized by CNO, illustrating that CNO was stimulating the PRAM pathway.
PRAM stimulation had a striking effect when rats were subjected to chronic darkness (8 weeks). Controls subjected to such conditions developed depressive-like behaviours in the forced swim test and the sucrose preference test. However, rats that received a daily injection of CNO did not exhibit a depressive-like phenotype. Therefore, PRAM stimulation was sufficient to eliminate the effect of darkness on mood.

They then assessed the effect of intraocular saporin toxin, which selectively ablates melanopsin-positive RGCs, on mood. They predicted that ablation of these neurons would elicit depressive-like behaviours in rats living in normal light conditions. Indeed, these rats exhibited a similar behavioural profile to rats that spent 8 weeks in darkness. They also had more apoptosis in the LC than controls who received a vehicle injection. Thus, ablation of melanopsin-positive RGCs imparts a depressive-like phenotype and this may be due to the effect on the PRAM pathway.
All in all, these experiments suggest that this PRAM pathway is implicated in light-related mood fluctuations.

Poster title: “Chemogenetic activation of a retinal circuit that activates locus coeruleus neurons prevents the development of light-deprivation induced depression-like behavior”
Presenter: Dr. Hannah Bowery

Geith Maal-Bared
PhD Candidate
van der Kooy Lab
University of Toronto
Neuronline: @GeithMB
Twitter: @GeithMB
Website: geithisms.com