Abstract
Key points Rhythmic processes in living organisms are controlled by biological clocks. The orexinergic system of the lateral hypothalamus carries circadian information to provide arousal for the brain during the active phase.Here, we show that orexins exert an excitatory action in three parts of the lateral geniculate nucleus (LGN), in particular upon directly retinorecipient neurons in the non‐image forming visual structures.We provide evidence for the high nocturnal levels of orexins with stable circadian expression of predominant orexin receptor 2 in the LGN.Our data additionally establish the convergence of orexinergic and pituitary adenylate cyclase (PAC)‐activating peptide/PAC1 receptor systems (used by melanopsin‐expressing retinal ganglion cells), which directly regulates responses to the retinal input.These results help us better understand circadian orexinergic control over the non‐image forming subcortical visual system, forming the animal's preparedness for the behaviourally active night. The orexinergic system of the lateral hypothalamus is tightly interlinked with the master circadian clock and displays daily variation in activity to provide arousal‐related excitation for the plethora of brain structures in a circadian manner. Here, using a combination of electrophysiological, optogenetic, histological, molecular and neuronal tracing methods, we explore a particular link between orexinergic and visual systems in rat. The results of the present study demonstrate that orexinergic fibre density at the area of subcortical visual system exerts a clear day to night variability, reaching a maximum at behaviourally active night. We also show pronounced electrophysiological activations of neurons in the lateral geniculate nucleus by orexin A through 24 h, via identified distinct orexin receptors, with the ventrolateral geniculate displaying a daily cycle of responsiveness. In addition, for the first time, we provide a direct evidence for orexins to act on retinorecipient neurons with a high convergence of orexinergic and putatively retinal pituitary adenylate cyclase (PAC)‐activating peptide/PAC1 receptor systems. Altogether, the present study ties orexins to non‐image forming visual structures with implications for circadian orexinergic modulation of neurons, which process information on ambient light levels.
Highlights
Most, if not all living organisms organize their physiological processes according to rhythmic environmental cues with a period of circa 24 h, as a consequence of specialized molecular mechanisms termed biological clocks (Hastings et al 2018; Challet, 2019)
Further inspection of thalamic/pretectal slices revealed an interesting pattern: OXB-ir fibres were dense/moderate at the area of retinorecipient structures involved in the non-visual processing, such as the intergeniculate leaflet (IGL), ventrolateral geniculate nucleus (VLG), olivary pretectal nucleus (OPT) and posterior limitans nucleus (PLi), and sparse in the DLG or other pretectal areas
The primary findings of the present study are: (i) the orexinergic system with the source in the lateral hypothalamus densely innervates non-image forming visual structures, with a higher nocturnal orexin availability than during the behaviourally quiescent day; (ii) orexins robustly excite IGL and VLG neurons, in contrast to relatively sparse responsiveness of the DLG in adult rats; (iii) OX2R is expressed throughout all three subareas of the LGN, whereas the co-expression of OX1R was seen in the IGL only; (iv) despite the lowered sensitivity to two-way ANOVA)
Summary
If not all living organisms organize their physiological processes according to rhythmic environmental cues with a period of circa 24 h, as a consequence of specialized molecular mechanisms termed biological clocks (Hastings et al 2018; Challet, 2019). The central circadian pacemaker is localized in the suprachiasmatic nucleus (SCN) of the hypothalamus, which is sensitive to ambient light levels as a result of rich innervation from the intrinsically photosensitive retinal ganglion cells (ipRGCs) expressing a ‘circadian photopigment’ melanopsin (Hattar et al 2002; Schmidt et al 2011). The orexinergic system of the lateral hypothalamus (de Lecea, 1998; Sakurai et al 1998) has been shown to tightly co-operate with the master clock, providing high levels of arousal during the active phase and being sensitive to ambient light (Peyron et al 1998; McGranaghan & Piggins, 2001; Marston et al 2008; Webb et al 2008; Belle et al 2014; Belle & Piggins, 2017; Karnani et al 2020). There is some evidence for both rodent and human retina to synthesize orexins and their receptors (orexin receptor 1 and 2; OX1R and OX2R) (Savaskan et al 2004; Liu et al 2011)
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