Biology subjects

Calligaro, H.

Publications and source records attributed to Calligaro, H..

5 recordsLinked to original sources

bioRxiv2026

The circadian system is affected by Alzheimers disease independently from amyloid beta deposits

Circadian disruption, notably sleep disturbances, serves as an early indicator of Alzheimers disease (AD), preceding cognitive symptoms like memory loss. The suprachiasmatic nucleus (SCN) governs biological rhythms and receives direct retinal input via melanopsin-expressing retinal ganglion cells (mRGCs) to synchronize with environmental light cycles. The anatomical and functional basis for circadian disruption in AD remains unclear. Here, we explored the multi-level relationships between gene expression, the SCN connectome, and regulations of sleep and circadian rhythms in the APP/PS1 mouse model. The sleep architecture of APP/PS1 mice displayed significantly reduced rapid eye movement sleep (REM), associated with a reduced daily core body temperature amplitude and locomotor hyperactivity. Lastly, APP/PS1 mice showed an impaired response to acute light pulse stimulation and present hyperactivity of mRGCs at a young age and hypoactivity of these cells at older ages. These physiological functions are known to be, at least in part, regulated by the SCN, the main target of mRGCs. We noted several modifications in SCN connectomics using serial blockface electron microscopy (SBEM), including a reduction of the dendro-dendritic chemical synapse (DDCS) network that receives a large part of the retinal input and is thought to be crucial for synchronicity between SCN neurons. In addition, we observed multiple signs of dystrophy, including modifications of the shape of dendrites and cell soma, accumulation of aggregated lysosomes, and swelling of axons. At the same time, we investigated the changes in gene expression using spatial transcriptomics. The SCN presents changes in the expression of genes associated with synapse formation, cell adhesion, and neurite growth. These results suggest that, despite the absence of amyloid plaques in the ventral hypothalamus, the SCN of APP/PS1 mice still undergo profound gene expression changes, impacting connectomics and physiological functions. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=157 SRC="FIGDIR/small/744599v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@ceedb0org.highwire.dtl.DTLVardef@156cfaaorg.highwire.dtl.DTLVardef@5bc262org.highwire.dtl.DTLVardef@36df4d_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

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↗

bioRxiv2022

Ultrastructure of synaptic connectivity within sub-regions of the SCN revealed by genetically encoded EM tag and SBEM

The suprachiasmatic nucleus (SCN) in the hypothalamus of the vertebrate brain is the central pacemaker regulating circadian rhythmicity throughout the body. The SCN receives photic information through melanopsin-expressing retinal ganglion cells (mRGC) to synchronize the body with environmental light cycles. Determining how these inputs fit into the network of synaptic connections on and between SCN neurons is key to impelling our understanding of the regulation of the circadian clock by light and unraveling the relevant local circuits within the SCN. To map these connections, we used a newly-developed Cre-dependant electron microscopy reporter, APEX2, to label mitochondria of mRGC axons, and serial blockface scanning electron microscopy to resolve the fine structure of mRGC in 3D volumes of the SCN. The maps thus created provide a first draft of the patterns of connectomic organization of SCN in the core and the shell, composed of different neuronal subtypes, and here shown to differ with regard to the patterning of their mRGC input as the shell receives denser mRGCs synaptic inputs compared to the core. This challenges the presently held view that photic information coming directly from the retina is mainly integrated by the core region of the SCN.

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

A clock in mouse cones contributes to the retinal oscillator network and to synchronization of the circadian system

The circadian system is a hierarchical network of cell and tissue-specific oscillators synchronized to the environmental light/dark cycle. Entrainment is mediated by the retina through diverse photosensitive cells and pigments. The retina is itself a complex circadian system whose cellular constitutive elements have not been fully characterized. By using the Nrl-/- cone gain-of-function mouse model we here show that the retinal network comprises an autonomous oscillator harbored in cones. We further provide novel evidence for an input from cones to the master clock, as revealed under constant light condition.

neuroscience↗