Biology subjects

Fraigne, J. J.

Publications and source records attributed to Fraigne, J. J..

3 recordsLinked to original sources

bioRxiv2026

Cell vulnerability within the sublaterodorsal tegmental nucleus underlies REM sleep behaviour disorder in prodromal α-synucleinopathy

REM sleep behaviour disorder (RBD) is a prodromal manifestation of -synucleinopathies such as Parkinsons disease. Evidence suggests that degeneration of REM sleep regulating neurons in the sublaterodorsal tegmental nucleus (SLD) could give rise to RBD, yet the specific cellular populations involved and their contribution to synucleinopathy progression remain unclear. Here, we investigated the role of defined SLD cell types in RBD pathogenesis. Using viral vector and fibril-based models of -synucleinopathy, we show that -synuclein pathology in SLD neurons triggers RBD in mice. Notably, glutamatergic SLD neurons are selectively vulnerable to synucleinopathy and the loss of these cells correlates with RBD severity. Propagation of synucleinopathy from the SLD to midbrain and forebrain structures leads to the emergence of neurological deficits associated with Parkinsons disease. These findings establish that SLD neurons are critical substrates for RBD and provide insight into the cellular mechanisms at play in the early stages of synucleinopathies.

neuroscience↗

bioRxiv2025

Molecular Logic of Cell Diversity and Circuit Connectivity in the REM Sleep Hub

The complexity of the brain arises from the diversity of its circuits and the molecular heterogeneity of the cells that compose them. A mechanistic understanding therefore requires mapping cellular identity and connectivity at single-cell resolution. Here we define the cellular taxonomy of the murine sublaterodorsal tegmental nucleus (SLD), a critical hub for REM sleep, using single-nucleus RNA sequencing. We identified all major brain cell classes, with oligodendrocytes as the most abundant, and resolved seventeen transcriptionally distinct neuronal groups defined by neurotransmitters, neuromodulators, and neuropeptides, each with unique molecular signatures. Projection-specific analysis further revealed that glutamatergic subpopulations targeting the ventrolateral periaqueductal gray (vlPAG) and ventral medulla are molecularly distinct, marked by characteristic receptor motifs. Strikingly, we provide the first direct evidence that SLDGLUT neurons innervate the vlPAG. This newly uncovered SLDGLUT[->]vlPAG pathway represents a previously unrecognized circuit node for REM sleep regulation, with the potential to act as a REM-OFF population suppressing it. Together, these findings establish a transcriptionally resolved atlas of the SLD, reveal the molecular logic of its circuit connectivity, and nominate candidate molecular actuators of REM sleep control, opening new avenues for dissecting how brainstem circuits orchestrate REM state and its transitions.

neuroscience↗

bioRxiv2025

GABA neurons in the sublaterodorsal tegmental (SLD) nucleus suppress wakefulness in wild-type and narcoleptic mice

The sleep-wake cycle is generated by competing neural circuits that control the oscillation between wakefulness, rapid eye movement (REM) sleep, and non-REM (NREM) sleep. While the sublaterodorsal tegmental nucleus (SLD) is recognized for its role in REM sleep generation, the functional contribution of its GABAergic neurons (SLDGABA) to sleep-wake regulation remains poorly understood. Here, we found that SLDGABA neurons function as a suppressor of wakefulness in both wild-type and narcoleptic mice. Optogenetic silencing of SLDGABA neurons rapidly induced robust wakefulness, while enhancing cortical and motor activity. Conversely, optogenetic activation of these neurons suppressed wakefulness and promoted NREM sleep. We found that SLDGABA neurons project extensively to wake-promoting brain regions, providing an anatomical basis for their wake-suppressing effects. Importantly, we discovered that SLDGABA neurons play a pathological role in narcolepsy: their activation in orexin-deficient mice triggered characteristic sleep attacks--rapid intrusions of NREM sleep during active wakefulness-- while silencing these neurons rescued animals from both sleep attacks and cataplexy. Collectively, these findings establish SLDGABA neurons as a key regulator of arousal state transitions and identify them as a novel therapeutic target for the treatment of narcolepsy.

neuroscience↗