Biology subjects

Dkhissi-Benyahya, O.

Publications and source records attributed to Dkhissi-Benyahya, O..

4 recordsLinked to original sources

bioRxiv2026

Divergent molecular and circuit mechanisms underlie light entrainment of retinal and suprachiasmatic nucleus circadian clocks

The circadian system aligns behavior and physiology with the 24-hour environmental cycle through a distributed network of clocks including the master pacemaker in the suprachiasmatic nucleus (SCN) and an autonomous retinal clock critical for local retinal physiology and function. Although both clocks are entrained by light, they differ in their photoreceptor inputs and light sensitivity. The specific contributions and mechanisms by which distinct photoreceptor pathways drive their photoentrainment, however, remain incompletely understood. In this study, we conducted a comprehensive transcriptomic and integrative comparative analysis of retinal and SCN circadian light responses using mouse models lacking specific photoreceptors or key components of signaling pathways. Under photopic conditions, we found that each tissue displays distinct light-responsive transcriptional signatures across genotypes, yet both shared a conserved cluster of rod-driven immediate early-genes. Strikingly, the light-evoked transcriptional response was not sufficient to shift the phase of the SCN clock, in contrast to its robust phase-shifting effect on the retinal clock. Furthermore, by genetically disrupting rod/cone electrical coupling and pharmacologically isolating rod pathways, we identified the OFF-cone bipolar cell circuit as both necessary and sufficient to mediate light-induced phase resetting of the retinal clock. Together, these findings delineate the specialized retinal circuitry that underlies circadian entrainment and reveal a fundamental divergence between retinal and SCN mechanisms of photic timekeeping.

neuroscience↗

bioRxiv2023

Mapping the daily rhythmic transcriptome in the diabetic retina

Retinal function shows marked changes from day to night. Yet, clinical diagnosis, treatments, and experimental sampling occur during the day, leaving a significant gap in our understanding of the pathobiology occurring at night. While there is evidence that diabetes disrupts the circadian system that optimizes our physiology to the environmental light/dark cycle, the impact of such disruption is not well understood. This study investigates whether diabetes affects the retinas daily rhythm of gene expression to understand the pathobiology of diabetic retinopathy. Ins2Akita/J mice, a model of type 1 diabetes, were kept under a standard 12h:12h light/dark cycle until four months of age. Non-diabetic littermates were used as controls. Bulk mRNA sequencing was conducted in retinas collected every 4 hours throughout the 24 hr light/dark cycle. Computational approaches were used to detect rhythmicity, predict acrophase, identify differential rhythmic patterns, analyze phase set enrichment, and predict upstream regulators. The retinal transcriptome exhibited a tightly regulated rhythmic expression with a clear 12-hr axis of transcriptional rush, peaking at midday and midnight. The functions of day-peaking genes were enriched for DNA repair, RNA splicing, and ribosomal protein synthesis, whereas night-peaking genes were enriched for metabolic processes and growth factor signaling. Although the 12-hr transcriptional axis is retained in the diabetic retina, it was phase advanced by approximately 1-3 hours with a wider distribution. Upstream regulator analysis for the genes that showed phase shifts identified oxygen sensing mechanisms and HIF1alpha as regulators, but not the circadian clock, which remained in phase to the light/dark cycle. We propose a model in which early in diabetes, the retina experiences a jet lag caused by the entrained circadian clock and its output being in one phase and metabolic pathways related to neuronal dysfunction and hypoxia driving advancement of gene expression to a different phase. Further studies are now required to evaluate the chronic implications of such internal jet lag for development of diabetic retinopathy.

bioinformatics↗

bioRxiv2021

Dopamine desynchronizes the retinal clock through a melanopsin-dependent regulation of acetylcholine retinal waves during development

Dopamine (DA) plays a critical role in retinal physiology, including resetting of the retinal circadian clock that in turn regulates DA release. DA acts on major classes of retinal cells by reconfiguring electrical and chemical synapses. Although a bidirectional regulation between intrinsically photosensitive melanopsin ganglion cells (ipRGCs) and dopaminergic cells has been demonstrated during development and adulthood, DA involvement in the ontogeny of the retinal clock is still unknown. Using wild-type Per2Luc and melanopsin knockout (Opn4-/-::Per2Luc) mice at different postnatal stages, we found that the retina can generate self-sustained circadian rhythms from postnatal day 5 that emerge in the absence of external time cues in both genotypes. Intriguingly, DA lengthens the endogenous period only in wild-type retinas, suggesting that this desynchronizing effect requires melanopsin. Furthermore, blockade of cholinergic retinal waves in wild-type retinas induces a shortening of the period, similarly to Opn4-/-::Per2Luc explants. Altogether, these data suggest that DA desynchronizes the retinal clock through a melanopsin-dependent regulation of acetylcholine retinal waves, thus offering a new role of melanopsin in setting the period of the retinal clock during development.

neuroscience↗

bioRxiv2020

Astroglia in lateral habenula is essential for antidepressant efficacy of light

Successful antidepressant (AD) treatments are still difficult to achieve. Recently, bright light stimulation (BLS) was shown effective in non-seasonal depression but its mode of action remains elusive. We demonstrate here, using a new mouse model of depression resistant to ADs including ketamine, that chemogenetic activation of lateral habenula (LHb) astroglia prevented the potentiating effect of BLS on the AD response. Additionally, the beneficial action of BLS was associated with upregulation of a specific part of the prefrontal cortex opioid system. These results show that improved behavioral outcome produced by BLS requires habenular astroglia and endogenous opioids as crucial buffer systems.

neuroscience↗