Inhibitory GABAergic neurons in the parafacial zone (PZGABA) are essential for slow wave sleep (SWS). Since existing literature about the heterogenous population of PZ neurons is lacking, questions remain regarding the non-GABAergic sleep active PZ neurons. This study seeks to determine if glutamatergic PZ neurons expressing the transcription factor Phox2B (PZPhox2B) participate in sleep-wake control. Phox2B-IRES-Cre mice received injections of adeno-associated virus containing Cre-dependent diphtheria toxin subunit A (DTA) DNA into the PZ (PZPhox2B-DTA). Analysis of injection sites revealed transfection covering the PZ and the locus coeruleus, also known to express Phox2B. We recorded the sleep-wake cycle of PZPhox2B-DTA mice and compared them with control mice, analyzing their sleep-wake quantity, fragmentation, and power spectral distribution. We found total amounts and cortical power for wakefulness, SWS, and REM sleep of PZPhox2B-DTA mice were unaffected. There was fragmentation in wakefulness during the active period for PZPhox2B-DTA mice, seen as a significant reduction in the amount of time and number of episodes spent in the longest bout; however, wakefulness during the rest period was not significantly altered. No significant change was found in the bout numbers and amounts for SWS and REM sleep of PZPhox2B-DTA mice. I was unable to confirm targeted ablation of PZPhox2B-DTA neurons due to a lack of reliable antibody staining. Therefore, it remains possible that ablation of PZPhox2B neurons was incomplete and the wakeful fragmentation is due to neuronal ablation outside of the PZ, such as in the neighboring LC.

Le syndrome d'ondine est une maladie génétique rare caractérisée par une hypoventilation pendant le sommeil, des apnées et une absence de réponse au CO2. La majorité des patients ont une mutation hétérozygote à expansion d'alanine du gène PHOX2B, important dans le développement du système nerveux autonome. Notre objectif est d'étudier le rôle de Phox2b dans le contrôle de la ventilation et de valider un modèle murin du syndrome d'Ondine. Grâce à une plateforme d'exploration fonctionnelle originale permettant les mesures non invasives dans un environnement contrôlé en température et en gaz des variables cardiorespiratoires chez le souriceau, nous avons analysé in vivo deux modèles de souris hétérozygotes pour Phox2b. Les souriceaux hétérozygotes Phox2b+/-, issus d'une invalidation d'un allèle Phox2b, présentent une instabilité ventilatoire associée à une activité tonique anormalement élevée de leurs chémorécepteurs périphériques. Leur phénotype ventilatoire dépend fortement de la température ambiante. La reproduction de la mutation humaine majoritaire, une insertion de 7 alanines (souriceaux Phox2b27Ala/+) chez le souriceau, produit un phénotype similaire au syndrome d'Ondine. Ces souriceaux meurent rapidement d'apnée centrale à la naissance. Ils ont une perte spécifique de neurones exprimant de neurones du noyau rétrotrapézoïde/groupe respiratoire parafacial (RTN/pFRG) impliqués dans la chémoréception centrale et la rythmogenèse, ce qui montre le rôle important du RTN/pFRG dans la chémosensibilité au CO2, et dans la rythmogénèse respiratoire néonatale / Ondine syndrome is a rare genetic disease characterized by hypoventilation during sleep, apneas and the absence of ventilatory response to CO2. The majority of patients carry a heterozygous mutation with polyalanine expansion of PHOX2B gene, which is important in the development of autonomous nervous system. We aim to study the role of Phox2b in ventilatory control and to validate a mouse model of Ondine syndrome. We used a platform that allows in vivo, non-invasive measurements of cardiorespiratory variables in newborn mice in controlled temperature and gas conditions. Heterozygous Phox2b+/- pups, which were obtained by invalidation of one allele of Phox2b, show ventilatory instability with augmented tonic activity of peripheral chemoreceptor. Their ventilatory phenotype strongly depends on ambient temperature. Reproducing in mice Phox2b mutation, which is frequently observed in patients, an insertion of 7 alanines (mutant pups Phox2b27Ala/+) produces a similar phenotype to Ondine syndrome. These newborn mice rapidly die of central apnea after birth. Phox2b27Ala/+ pups have a specific loss of neurons expressing Phox2b in retrotrapezoïd nucleus/parafacial respiratory group (RTN/pFRG) involved in central chemoreception and in rhythmogenesis, showing the important role of RTN/pFRG in CO2 chemosensitivity, and in respiratory rhythmogenesis at birth

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