Glutathione deficit impairs myelin maturation: relevance for white matter integrity in schizophrenia patients

Schizophrenia pathophysiology implies both abnormal redox control and dysconnectivity of the prefrontal cortex, partly related to oligodendrocyte and myelin impairments. As oligodendrocytes are highly vulnerable to altered redox state, we investigated the interplay between glutathione and myelin. In control subjects, multimodal brain imaging revealed a positive association between medial prefrontal glutathione levels and both white matter integrity and resting-state functional connectivity along the cingulum bundle. In early psychosis patients, only white matter integrity was correlated with glutathione levels. On the other side, in the prefrontal cortex of peripubertal mice with genetically impaired glutathione synthesis, mature oligodendrocyte numbers, as well as myelin markers, were decreased. At the molecular levels, under glutathione-deficit conditions induced by short hairpin RNA targeting the key glutathione synthesis enzyme, oligodendrocyte progenitors showed a decreased proliferation mediated by an upregulation of Fyn kinase activity, reversed by either the antioxidant N-acetylcysteine or Fyn kinase inhibitors. In addition, oligodendrocyte maturation was impaired. Interestingly, the regulation of Fyn mRNA and protein expression was also impaired in fibroblasts of patients deficient in glutathione synthesis. Thus, glutathione and redox regulation have a critical role in myelination processes and white matter maturation in the prefrontal cortex of rodent and human, a mechanism potentially disrupted in schizophrenia

The role of milk odor in mother - newborn olfactory communication in the mouse and human

Chez la souris et l’humain, le lait véhicule un facteur odorant qui déclenche des réponses d’attraction et d’appétence chez les nouveau-nés. Dans le but d’identifier la nature chimique des composés volatils responsables de ce pouvoir réactogène, des mises au point techniques ainsi que plusieurs stratégies expérimentales ont été proposées au cours de ce travail doctoral. Tout d’abord, pour les deux modèles, les tests comportementaux ont été adaptés dans le but de présenter des substrats sous forme d’effluves dynamiques. Ensuite, chez le modèle murin, nous avons standardisé des conditions de conservation dans lesquelles le lait murin perd son potentiel réactogène. Ainsi, nous avons observé qu’à 4°C, le lait se conserve 3h, mais qu’après 24h de conservation, il perd totalement son potentiel réactogène. À -80°C, sa conservation s’étend jusqu’à 1 mois, mais après 8 mois, le potentiel réactogène est aboli. Ces résultats permettent à présent de comparer le profil chimique de laits frais réactogènes avec celui de laits inactivés (non-réactogènes) afin d’identifier les composés volatils ayant varié. Le rôle des glandes papillaires dans la sécrétion du facteur odorant réactogène du lait murin a aussi été étudié. Nous avons mis au point un protocole de lavage permettant de récolter les sécrétions de ces glandes et avons observé qu’elles étaient particulièrement attractives et appétitives pour les souriceaux.Chez l’humain, nous avons montré que les nouveau-nés de 2 jours sont capables de distinguer l’odeur du colostrum de celle du lait mature et qu’ils préfèrent le premier (qui correspond à leur âge). Ensuite, dans le but de commencer à valider un essai olfactif néonatal, nous avons aussi caractérisé les réponses comportementales et psychophysiologiques engendrées par l’odeur du colostrum chez les nouveau-nés et adapté nos tests pour présenter des substrats sous forme d’effluves dynamiques. Des mimiques d’appétence ainsi qu’une décélération cardiaque ont été observées lorsque l’odeur du colostrum frais est présentée. Ces réponses sont spécifiques au colostrum (en comparaison à un autre odorant – la vanille) et ce, peu importe le mode de présentation des odeurs (de façon statique avec un coton-tige ou par un flux d’air administré à l’aide d’une seringue). Finalement, grâce à nos prélèvements, des analyses chimiques comparant les composés volatils d’échantillons individuels de colostrum humain sont en cours pour l’’identification ultérieure d’invariants odorants propres au lait humain.In both humans and mice, milk conveys an odor factor that triggers attraction and appetitive responses in newborns. In order to identify the chemical nature of the volatile compounds responsible for such behavioral effects, technical improvements as well as several experimental strategies have been set up. First, for both murine and human models, behavioral assays have been adapted to deliver olfactory stimuli through a dynamic airflow. Secondly, in the murine model, we have defined storage conditions in which the murine milk loses its reactogenic potency. We observed that murine milk remains reactogenic when stored at 4°C for 3h but it completely loses its potency after 24h. At -80°C, its preservation is extended up to 1 month, but after 8 months of storage, the reactogenic potency of murine milk is entirely lost. This will allow us to compare the chemical profile of fresh reactogenic milk with the one of inactive milk, and to identify the volatiles that have varied. The role of the papillary glands in the reactogenic potency of milk odor has also been investigated in the mouse. We set up a washing procedure which allows us to collect the glands secretions and we found out that they are particularly attractive and appetitive to 2-day old mouse pups.In the human model, we have shown that 2 day-old newborns discriminate between the odors of colostrum and of mature milk, and that they prefer the former to the latter. We also characterised the behavioral and psychophysiological responses of newborns to the odor of colostrum in order to validate an olfactory bioassay. Moreover this bioassay was adapted so that we could deliver the olfactory substrates using a static or a dynamic delivery method. Some appetitive oral responses as well as a deceleration in heart rate frequency were observed when fresh colostrum odor was presented. Such responses were specific to colostrum (in comparison to another odorant – vanilla) and were observed with both delivery method (static method with a cotton-swab or a dynamic method with a syringe). Finally, chemical analyses comparing the volatile compounds of several individual colostrum samples are being carried on

Adaptive value of maternal odors in human neonates

International audienc

Attractive and appetitive odor factors in murine milk: Their fade-out time and differential cryo-preservation

International audienceMurine milk conveys an odor factor that is both attractive and appetitive to conspecific newborns. Up to now, little is known about the temporal dynamic of this odor factor and about the stability of its behavioral activity after milk ejection. We aim to characterize the conditions in which the attractive and appetitive potency of milk to newborns is best conserved and, as a logical outcome, at standardizing conditions in which milk varies in reactogenic potency for newborns. Milk was collected and conserved in two conditions of cold (4 degrees C, -80 degrees C) for several durations (3 and 24h, and 1, 2 and 8 months). The reactogenic potency of milk was assayed in 2 day-old mouse pups. We found that milk remains olfactorily attractive and appetitive to newborns after 3h of storage at 4 degrees C, but it completely loses reactogenic potency on newborn pups after 24h of storage at 4 degrees C. Storage at -80 degrees C preserves the behavioral activity of milk up to 1 month, but milk stored for 2 months at this temperature remains appetitive but not attractive to pups. Finally, the reactogenic potency of murine milk in pups is abolished after 8 months of storage at -80 degrees C. This study highlights that attractive and appetitive factors of milk appear dissociable and, in any case, highly labile. It provides, for two different storage temperatures, a temporal window in which milk remains behaviorally active on pups. These results will allow designing a contrastive chemical approach to identify the reactogenic compounds of milk

The role of papillary skin glands in guiding mouse pups to the nipple

International audienceThe nipple odor of lactating mice (Mus musculus) plays a crucial role in attracting newborn pups and motivating them to suck milk. The characteristic odor of a lactating murine nipple is assumed to be a mixture of multiple odorous substrates, that is, milk, dam's and pups' saliva, skin glands' secretions, and amniotic fluid. The present study aimed to characterize the behavioral activity of the original odor mixture that develops over the nipples in the first 2 days postpartum. We extracted this odor mixture in water and evaluated its attractive and appetitive potencies using two behavioral assays (viz., relative attraction and oral activation assays). It resulted that the so-called nipple wash was as appetitive as fresh milk, and even more attractive than it. The behavioral potency of the nipples was shown to be specific to lactating nipples (relative to nulliparous nipples) and to be preserved for 2 weeks when stored at -80°C. Finally, we perfected a nipple deodorization procedure by inactivating the nipples' behavioral potency. We observed that such altered appetitive potency was fully restored 30 min after its washing, but without any maternal self-licking and pups' sucking, indicating that the secretions of the nipple skin glands' were sufficient to explain the success of neonatal guidance to the nipple

Caractérisation de quelques substrats mammaires odorants impliqués dans le succès de la tétée des souriceaux

National audienc

Une alimentation maternelle enrichie en gras pendant la gestation ou l’allaitement oriente les préférences du souriceau vers un aliment gras à la naissance et au sevrage

National audienc

Human neonates prefer colostrum to mature milk: Evidence for an olfactory bias toward the “initial milk”?

International audienceOBJECTIVES: Colostrum is the initial milk secretion which ingestion by neonates warrants their adaptive start in life. Colostrum is accordingly expected to be attractive to newborns. The present study aims to assess whether colostrum is olfactorily attractive for 2-day-old newborns when presented against mature milk or a control. METHODS: The head-orientation of waking newborns was videotaped in three experiments pairing the odors of: (a) colostrum (sampled on postpartum day 2, not from own mother) and mature milk (sampled on average on postpartum day 32, not from own mother) (n tested newborns = 15); (b) Colostrum and control (water; n = 9); and (c) Mature milk and control (n = 13). RESULTS: When facing the odors of colostrum and mature milk, the infants turned their nose significantly longer toward former (32.8 vs 17.7% of a 120-s test). When exposed to colostrum against the control, they responded in favor of colostrum (32.9 vs 16.6%). Finally, when the odor of mature milk was presented against the control, their response appeared undifferentiated (26.7 vs 28.6%). CONCLUSIONS: These results indicate that human newborns can olfactorily differentiate conspecific lacteal fluids sampled at different lactation stages. They prefer the odor of the mammary secretion - colostrum - collected at the lactation stage that best matches the postpartum age of their own mother. These results are discussed in the context of the earliest mother-infant chemo-communication. Coinciding maternal emission and offspring reception of chemosignals conveyed in colostrum may be part of the sensory precursors of attunement between mothers and infants

Testing detectability, attractivity, hedonic specificity, extractability, and robustness of colostrum odor—Toward an olfactory bioassay for human neonates

International audienceHuman milk odor is attractive and appetitive for human newborns. Here, we studied behavioral and heart‐rate (HR) responses of 2‐day‐old neonates to the odor of human colostrum. To evaluate detection in two conditions of stimulus delivery, we first presented the odor of total colostrum against water. Second, the hedonic specificity of total colostrum odor was tested against vanilla odor. Third, we delivered only the fresh effluvium of colostrum separated from the colostrum matrix; the stability of this colostrum effluvium was then tested after deep congelation; finally, after sorptive extraction of fresh colostrum headspace, we assessed the activity of colostrum volatiles eluting from the gas chromatograph (GC). Regardless of the stimulus‐delivery method, neonates displayed attraction reactions (HR decrease) as well as appetitive oral responses to the odor of total colostrum but not to vanilla odor. The effluvium separated from the fresh colostrum matrix remained appetitive but appeared labile under deep freezing. Finally, volatiles from fresh colostrum effluvium remained behaviorally active after GC elution, although at lower magnitude. In sum, fresh colostrum effluvium and its eluate elicited a consistent increase in newborns’ oral activity (relative to water or vanilla), and they induced shallow HR decrease. Newborns’ appetitive oral behavior was the most reproducible response criterion to the effluvium of colostrum. In conclusion, a set of unidentified volatile compounds from human colostrum is robust enough after extraction from the original matrix and chromatographic processing to continue eliciting appetitive responses in neonates, thus opening new directions to isolate and assay specific volatile molecules of colostrum