Orexin-A Suppresses Signal Transmission to Dopaminergic Amacrine Cells From Outer and Inner Retinal Photoreceptors

Abstract

PurposeThe neuropeptides orexin-A and orexin-B are widely expressed in the vertebrate retina; however, their role in visual function is unclear. This study investigates whether and how orexins modulate signal transmission to dopaminergic amacrine cells (DACs) from both outer retinal photoreceptors (rods and cones) and inner retinal photoreceptors (melanopsin-expressing intrinsically photosensitive retinal ganglion cells [ipRGCs]).MethodsA whole-cell voltage-clamp technique was used to record light-induced responses from genetically labeled DACs in flat-mount mouse retinas. Rod and cone signaling to DACs was confirmed pharmacologically (in wild-type retinas), whereas retrograde melanopsin signaling to DACs was isolated either pharmacologically (in wild-type retinas) or by genetic deletion of rod and cone function (in transgenic mice).ResultsOrexin-A attenuated rod/cone-mediated light responses in the majority of DACs and inhibited all DACs that exhibited melanopsin-based light responses, suggesting that exogenous orexin suppresses signal transmission from rods, cones, and ipRGCs to DACs. In addition, orexin receptor 1 antagonist SB334867 and orexin receptor 2 antagonist TCS OX229 enhanced melanopsin-based DAC responses, indicating that endogenous orexins inhibit signal transmission from ipRGCs to DACs. We further found that orexin-A inhibits melanopsin-based DAC responses via orexin receptors on DACs, whereas orexin-A may modulate signal transmission from rods and cones to DACs through activation of orexin receptors on DACs and their upstream neurons.ConclusionsOur results suggest that orexins could influence visual function via the dopaminergic system in the mammalian retina.

Circadian actions of orexins on the retinorecipient lateral geniculate complex in rat

“…The LH/PFa constitutes the main source of orexins in the central nervous system, with few orexin-synthesizing neurons in the adjacent dorsolateral nucleus of the hypothalamus (Peyron et al 1998;Nambu et al 1999). However, both orexins and orexin receptors were reported to be expressed in the retina, including retinal ganglion cells, and they plausibly act as local neurotransmitters (Liu et al 2011;Qiao et al 2017;Zhang et al 2018). Here, we show that OXB is most probably not transported along the optic nerve because OXB immunoreactivity was not seen either in the retinal terminals labelled with the intraocular-injected CtB or in the optic tract.…”

“…Therefore, it has been hypothesized that orexins (orexin A and B; OXA and OXB) may act as hands of the clock for these brain systems that are not directly innervated by the SCN. Previous studies link the orexinergic system with the visual one, showing orexinergic innervation of the visual thalamus (Peyron et al 1998;McGranaghan & Piggins, 2001;Mintz et al 2001) and orexin sensitivity in the retina (Qiao et al 2017;Zhang et al 2018), three parts of the…”

“…2001) and orexin sensitivity in the retina (Qiao et al . 2017; Zhang et al . 2018), three parts of the LGN (Pekala et al .…”

Light-dependent pathways for dopaminergic amacrine cell development and function

“…To do this, we counted TH+ cells in retinas from littermate mice lacking functional rod ( Gnat1 -/- , hereafter referred to as RKO), cone ( Gnat2 cpfl3/cpfl3 , hereafter referred to as CKO), or melanopsin ( Opn4 -/- , hereafter referred to as MKO) phototransduction cascades ( Figure 2B ). Despite reports of ipRGC influence on DA-dependent retinal physiology ( Prigge et al, 2016 ; Zhang et al, 2008 ; Zhao et al, 2017 ; Zhang et al, 2012 ; Qiao et al, 2017 ), we found that MKO and CKO mice showed no significant change in TH+ cell number (MKO: Mean ± SEM = 615.3±55.5 cells, n = 6 retinas; CKO: Mean ± SEM = 708.6 ± 30.74 cells, n = 9 retinas; Control Mean ± SEM = 627.4 ± 13.5 cells, n = 9 retinas; One-Way ANOVA, Dunnett’s multiple comparisons test) or DA levels (MKO: Mean ± SEM = 3.63 ± 0.15 ng/mg, n = 6 retinas; CKO: Mean ± SEM = 3.88 ± 0.07 ng/mg, n = 6 retinas; Control Mean ± SEM = 3.55 ± 0.22 ng/mg, n = 6 retinas; One-Way ANOVA, Dunnett’s multiple comparisons test), though CKO mice showed a trend toward increasing numbers of TH+ cells ( Figure 2C–D ). These data indicate that lack of melanopsin or cone phototransduction does not influence basal retinal DA as previously suggested ( Dkhissi-Benyahya et al, 2013 ).…”

Daily orexinergic modulation of the rat superficial layers of the superior colliculus – implications for intrinsic clock activities in the visual system

“…The orexinergic system modulates neuronal activity of the subcortical visual system, including the lateral geniculate nucleus of the thalamus [18][19][20][21][22]24,45] and the SCN [46][47][48]. Orexins were also found to potently excite neurons in the visual cortex [49] and act at the level of the retina [50,51].…”