Blockade of the Retinal Orexin Receptors Affects Retinal and Hypothalamic C-fos Expression and Hypothalamic Rhythmicity in Male Wistar Rats

Abstract

Abstract Orexin A and B (OXA and OXB) and their receptors are expressed in the majority of retinal neurons in humans, rats, and mice. Orexins modulate signal transmission between the different layers of the retina. The suprachiasmatic nucleus (SCN) and the retina are central and peripheral components of the body's biological clocks; respectively. The SCN receives photic information from the retina through the retinohypothalamic tract (RHT) to synchronize bodily functions with environmental changes. In present study, we aimed to investigate the impact of inhibiting retinal orexin receptors on the expression of retinal Bmal1 and C-fos, as well as hypothalamic C-fos, Bmal1, Vip, and PACAP at four different time-points (Zeitgeber time; ZT 3, 6, 12, and ZT-24). The intravitreal injection (IVI) of OX1R antagonist (SB-334867) and OX2R antagonist (JNJ-10397049) significantly up-regulated C-fos expression in the retina. Additionally, compared to the control group, the combined injection of SB-334867 and JNJ-10397049 showed a greater increase in retinal expression of this gene. In addition, the expression of hypothalamic Vip and PACAPwas significantly up-regulated in both the SB-334867 and JNJ-10397049 groups. In contrast, the expression of Bmal1 was down-regulated. Finally, the expression of hypothalamic C-fos was down-regulated in all groups treated with SB-334867 and JNJ-10397049. This study is the first to investigate the impact of retinal orexin receptors on regulating rhythmicity in the retina and hypothalamus. These findings could give a new dimension to the understanding of disorders associated with circadian imbalances such as sleep, and the development of neurodegenerative disorders, like Alzheimer's.