EVOLUTION WITH AGING OF SLEEP MICROARCHITECTURE IN MICE ACCUMULATING NEUROMELANIN IN CATECHOLAMINERGIC NEURONS, A NEW HUMANIZED PARKINSON’S DISEASE MODEL - Archive ouverte HAL Accéder directement au contenu
Poster De Conférence Année : 2023

EVOLUTION WITH AGING OF SLEEP MICROARCHITECTURE IN MICE ACCUMULATING NEUROMELANIN IN CATECHOLAMINERGIC NEURONS, A NEW HUMANIZED PARKINSON’S DISEASE MODEL

Résumé

Parkinson’s disease (PD) is characterized by a preferential degeneration in substantia nigra (SN) and locus coeruleus (LC) of catecholaminergic neurons accumulating during life the dark-brown cytoplasmic pigment neuromelanin (NM). Since NM is not naturally produced in most animals, we generated a mouse line based on the tissue-specific constitutive expression of human NM-synthesizing enzyme tyrosinase (Tyr) under the tyrosine hydroxylase promoter (Tg-TH-Tyr). As in humans, Tg-TH-Tyr mice age-dependently accumulate NM in all catecholaminergic brain cell groups. In parallel to NM intracellular buildup, mice exhibit an early cell death in LC that precedes cell dysfunction in SN and PD-like manifestations of motor and non- motor deficits, thus founding a relevant humanized PD model. Here we assessed whether Tg-TH-Tyr mice may develop with aging sleep alteration and REM sleep behavior disorder (RBD, i.e. loss of muscle atonia with dream enactments during REM sleep), a well-documented prodromal parasomnia in PD patients, presumably linked to a degeneration of the LC/subcoeruleus area critical for REM sleep. At 8 months, Tg-TH-Tyr (n=8) and WT (n=7) mice were conventionally prepared for polysomnography with 3 EEG screws fixed to skull (cerebellum, parietal and frontal cortex) and 2 EMG electrodes inserted between nuchal muscles. Mice were recorded every 3 weeks until natural death (±20 months, n=5 Tg and 6 WT mice). Using EEG/ EMG signals, states were visually classified as Waking, Slow Wave Sleep (SWS) and REM sleep to quantify standard parameters. We observed that Tg-TH-Tyr (vs. WT) mice depicted early (since first recording weeks) marked alterations in sleep architecture (ultradian-circadian- day/night rhythms of REM sleep and SWS). Using non-parametric non-linear regression method (loess regression) combined to a general additive mixed model (GAMM) for all collected data across age (12 months), we observed that sleep alterations were maintained with aging without noticeable recovery nor aggravation compared to WT mice, likely indicative of a genotype-dependent precocious and irreversible impact (premature sleep aging) of NM accumulation and/or early LC neurodegeneration. Ongoing spectral EEG analyses will help to determine whether sleep quality is also abnormally affected by aging in Tg-TH-Tyr vs. WT mice. Finally, in-depth analyses of EMG signals in Tg-Th-Tyr mice did not evidence any aging effects on tonic or phasic RBD-like motor events during REM sleep.
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Dates et versions

hal-04178056 , version 1 (07-08-2023)

Identifiants

  • HAL Id : hal-04178056 , version 1

Citer

Patrice Fort, Romain Bouet, Maxime Grenot, Jiong Liu, Nuria Peñuelas, et al.. EVOLUTION WITH AGING OF SLEEP MICROARCHITECTURE IN MICE ACCUMULATING NEUROMELANIN IN CATECHOLAMINERGIC NEURONS, A NEW HUMANIZED PARKINSON’S DISEASE MODEL. NeuroFrance 2023, May 2023, Lyon, France. ⟨hal-04178056⟩
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