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Lignos, L.

Publications and source records attributed to Lignos, L..

2 recordsLinked to original sources
bioRxiv2025

The selective amyloid-driven failure of cholinergic medial septal neurons in aging mice perturbs REM sleep, cognition and emotion, and broadcasts amyloid to other brain regions

In humans, decreases in rapid eye movement sleep (REMS) strongly predict Alzheimers disease (AD), alongside early degeneration of basal forebrain cholinergic neurons. We examined how {beta}-amyloid pathology gradually erodes mouse cholinergic neurons. The familial AppNL-G-F allele was selectively expressed in medial septal (MS) cholinergic neurons of both sexes and compared with mice with global AppNL-G-F expression and selective genetic lesions of MS cholinergic cells. By 14 months, targeted AppNL-G-F allele expression had caused loss of 25% of MS cholinergic neurons and produced amyloid deposition in their terminal fields, particularly the hippocampus. REMS was reduced, together with cognitive and emotional alterations mirroring phenotypes in global mutants, which also showed selective MS cholinergic cell loss. Genetic lesioning of MS cholinergic cells recapitulated most phenotypes, identifying cholinergic loss, not amyloid deposition, as a probable cause of these phenotypes. Nevertheless, broadcasted amyloid from MS cholinergic neurons likely induced hippocampal astrocyte activation and epileptiform spikes. HighlightsO_LIAmyloid in medial septum causes cholinergic neuron loss and Alzheimers symptoms C_LIO_LIAmyloid from medial septal axons may trigger pathology in distant brain regions C_LIO_LILoss of acetylcholine, not amyloid spread, drives REM sleep and cognitive deficits C_LIO_LIBroadcasted septal amyloid induces hippocampal astrogliosis and epileptiform spikes C_LI GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=161 SRC="FIGDIR/small/663930v2_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@147275dorg.highwire.dtl.DTLVardef@69745borg.highwire.dtl.DTLVardef@1560ddborg.highwire.dtl.DTLVardef@a7d8d6_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗
bioRxiv2021

Nitric oxide synthase neurons in the preoptic hypothalamus are sleep-active and contribute to regulating NREM and REM sleep and lowering body temperature.

When mice are exposed to external warmth, nitric oxide synthase (NOS1) neurons in the median and medial preoptic (MnPO/MPO) hypothalamus induce sleep and concomitant body cooling. However, how these neurons regulate baseline sleep and body temperature is unknown. Using calcium photometry, we show that NOS1 neurons in MnPO/MPO are predominantly NREM active. This is the first instance of a predominantly NREM-active population in the PO area, or to our knowledge, elsewhere in the brain. In addition to releasing nitric oxide, NOS1 neurons in MnPO/MPO can release GABA, glutamate and peptides. We expressed tetanus-toxin light-chain in MnPO/MPO NOS1 cells to reduce vesicular release of transmitters. This induced changes in sleep structure: over 24 hours, mice had less NREM sleep in their dark (active) phase, and more NREM sleep in their light (sleep) phase. REM sleep episodes in the dark phase were longer, and there were fewer REM transitions between other vigilance states. REM sleep had less theta power. Mice with synaptically blocked MnPO/MPO NOS1 neurons were also warmer. In particular, mice were warmer than control mice at the dark-light transition (ZT0), as well as during the dark phase siesta (ZT16-20), where there is usually a body temperature dip. Also, at this siesta point of cooled body temperature, mice usually have more NREM, but mice with synaptically blocked MnPO/MPO NOS1 cells showed reduced NREM sleep at this time. Overall, MnPO/MPO NOS1 neurons promote both NREM and REM sleep and contribute to chronically lowering body temperature, particularly at transitions where the mice normally enter NREM sleep.

neuroscience↗