Khov, B. | Search bioRxiv

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

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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↗