Biology subjects

Haddjeri, N.

Publications and source records attributed to Haddjeri, N..

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↗

bioRxiv2025

Ketamine strengthens synaptic inputs to the dorsal raphe to boost serotonergic activity: pivotal for rapid antidepressant-like effects

Ketamine at subanaesthetic dose is known as a fast-acting antidepressant (AD), able to facilitate synaptic plasticity in the medial prefrontal cortex (mPFC) or the hippocampus. However, its influence on the serotonergic (5-HT) system is more confusing as it loses its behavioral effects in 5-HT-depleted animals, but does not modify 5-HT neuron function. We hypothesized that this discrepancy was due to the different temporal scales chosen in the related studies. We performed electrophysiological recordings of 5-HT neurons in the dorsal raphe nucleus (DRN) and microdialysis measurements of 5-HT release in the ventral hippocampus of male Sprague-Dawley rats. Experiments were designed to collect the results over a long duration, i.e. 4-5 hours after the injection. Levels of the pro-neuroplastic factors PSD-95 and Synapsin-1 in the DRN were also assessed, as was cell proliferation in the dentate gyrus (DG). 5-HT neuron mean firing rate was unmodified within the 2 h that followed ketamine (10 mg/kg, i.p.), but strongly (90%) increased in the 2-5 h time bin, an effect abolished by lesioning the mPFC or administering the mTOR inhibitor Torin-2. A similar kinetics was found for hippocampal 5-HT release. Synapsin-1 and PSD-95 mRNA transcriptions were enhanced at 2 h, and PSD-95 protein levels appeared to peak at 24 h. Finally, DG mitogenesis was enhanced 48 h post-injection, an augmentation suppressed in 5-HT-depleted animals. Low-dose ketamine provokes a "neuroplastic wave" originating in the mPFC and emerging in the hippocampus, a transfer in which the 5-HT system appears to act as an integrative hub of plasticity. SIGNIFICANCE STATEMENTThis study helps reconcile two theories, often opposed to explain antidepressant (AD) action: the "serotonergic hypothesis" proposing that AD efficacy primarily results from an increase of serotonin, and the "neuroplastic theory" whereby only significant changes in brain connectivity can explain mood improvement. Here we show that ketamine, a drug exerting AD effects much faster than classical molecules do, augments synaptic strength onto serotonergic neurons, which subsequently triggers an elevation of serotonin. In turn, this enhanced serotonergic neurotransmission leads to the production of new neurons in the hippocampus, therefore reshaping the circuitry of this brain area. The serotonergic system appears to transfer the neuroplastic changes induced by ketamine across the brain, thus behaving like an integrative hub for its AD action.

neuroscience↗

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↗