Summary
Blocking orexin receptors (OX1R and OX2R) in the retina significantly alters expression of key circadian clock genes in both the retina and hypothalamus, suggesting that retinal orexin signaling plays an important modulatory role in synchronizing peripheral and central biological clocks. These findings open potential new therapeutic targets for circadian rhythm disorders and conditions linked to circadian dysfunction, including sleep disorders and neurodegenerative diseases like Alzheimer's.
Key Findings
- Intravitreal injection of OX1R antagonist (SB-334867) and OX2R antagonist (JNJ-10397049) significantly up-regulated C-fos expression in the retina at multiple zeitgeber time points (ZT 3, 6, 12, 24).
- Combined blockade of OX1R and OX2R produced a greater increase in retinal C-fos expression than either antagonist alone.
- Hypothalamic VIP and PACAP expression was significantly up-regulated following both OX1R and OX2R antagonist treatment.
- Hypothalamic and retinal Bmal1 expression was significantly down-regulated in antagonist-treated groups.
- Hypothalamic C-fos expression was down-regulated across all antagonist-treated groups, indicating disrupted SCN activity rhythmicity.
Categories
Sleep & Circadian Health: Retinal orexin receptor blockade disrupts circadian gene expression (Bmal1, C-fos, VIP, PACAP) in both retina and SCN/hypothalamus, linking peripheral and central clock regulation.
The Science of Light: Demonstrates a novel retinal orexin signaling pathway that modulates retinohypothalamic tract communication and hypothalamic rhythmicity, expanding understanding of non-photoreceptor photic signal processing.
Dementia & Elder Care: Authors suggest findings may inform understanding of circadian disruption in neurodegenerative disorders such as Alzheimer's disease.
Author(s)
M Haddad, H Khazali, M Janahmadi, H Ghanbarian
Publication Year
2023
Related Publications
Sleep & Circadian Health
- Phototransduction by retinal ganglion cells that set the circadian clock
- The mammalian circadian timing system: organization and coordination of central and peripheral clocks
- The twoāprocess model of sleep regulation: a reappraisal
- Melanopsin is required for non-image-forming photic responses in blind mice
- Strange vision: ganglion cells as circadian photoreceptors
The Science of Light
- Phototransduction by retinal ganglion cells that set the circadian clock
- Color appearance models
- The mammalian circadian timing system: organization and coordination of central and peripheral clocks
- Diminished pupillary light reflex at high irradiances in melanopsin-knockout mice
- Melanopsin is required for non-image-forming photic responses in blind mice
Dementia & Elder Care
- Light therapy and Alzheimer's disease and related dementia: past, present, and future
- New strategies for neuroprotection in glaucoma, a disease that affects the central nervous system
- Sleep and circadian rhythms in Parkinson's disease and preclinical models
- Chronobioengineering indoor lighting to enhance facilities for ageing and Alzheimer's disorder
- The clock is ticking. Ageing of the circadian system: from physiology to cell cycle